Metabolism Research Center

San Donato di Ninea, Italy

Metabolism Research Center

San Donato di Ninea, Italy
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Benedini S.,University of Milan | Benedini S.,Endocrinology Unit | Dozio E.,University of Milan | Invernizzi P.L.,University of Milan | And 9 more authors.
Journal of Diabetes Research | Year: 2017

We compared irisin levels among groups of differently trained healthy individuals to explore the role of irisin as a physiological linker between exercise and metabolic health. Irisin and biochemical parameters of glucose and lipid metabolism were assessed in 70 healthy volunteers stratified for sport performance level into four groups: (1) 20 elite athletes of national level, (2) 20 subelite athletes of local level, (3) 20 recreational athletes, and (4) 10 sedentary subjects. All biochemical parameters were within the ranges of normality. Fasting glucose, HOMA-IR, and total cholesterol levels were inversely related to the degree of physical activity. HbA1c was higher in elite athletes compared to all the other groups (p<0.01). A U-shaped relation between free fatty acids and the degree of physical activity was observed. All groups showed similar plasma irisin levels. After correction for the degree of insulin resistance (irisin/HOMA-IR), elite athletes showed higher levels compared to sedentary and recreational subjects (p<0.01 and p<0.05, resp.). In addition, the number of metabolic parameters correlated with irisin increased at increasing the training status. Our study suggests a correlation between sport performance, insulin sensitivity, and irisin levels. Irisin may be one potential mediator of the beneficial effects of exercise on metabolic profile. Copyright © 2017 Stefano Benedini et al.


Adamo M.,University of Milan | Adamo M.,Metabolism Research Center | Codella R.,University of Milan | Codella R.,Metabolism Research Center | And 11 more authors.
Cell Transplantation | Year: 2017

Previous studies in humans with type 1 diabetes mellitus (T1D) and in nonobese diabetic mice have investigated the beneficial immunomodulatory potential of aerobic physical activity. Performing high volume of aerobic exercise may favorably regulate autoimmunity in diabetes. We tested whether increased physical activity is a self-sufficient positive factor in T1D subjects. During a 3-month observational period, active (six males; 40.5 ± 6.1 years; BMI: 24.5 ± 2.1) and sedentary (four males, three females; 35.9 ± 8.9 years; BMI: 25.7 ± 3.8) T1D individuals on insulin pump therapy were studied for metabolic, inflammatory, and autoimmune parameters. At baseline and at the end of a 3-month period, glycosylated hemoglobin (HbA1c), autoantibodies (anti-GAD, anti-ZnT8, anti-IA2, and ICA) and proinflammatory cytokines (IL-6 and TNF-a) were evaluated. During the third month of the period, physically active T1D patients showed a significant reduction in the average glucose levels (−9%, p = 0.025, by CGM) compared to the first month values, and even their hyperglycemic episodes (>180 mg/dl) diminished significantly (−24.2%, p = 0.032 vs. first month). Moreover, active T1D subjects exhibited an improved body composition with respect to sedentary controls. No significant changes were detected as to the autoimmune and inflammatory profiles. This study confirms the beneficial role of physical exercise associated with insulin pump therapy in order to improve metabolic control in individuals with T1D. These preliminary positive observations need to be challenged in a prolonged interventional follow-up. © 2017 Cognizant, LLC.


Codella R.,University of Milan | Terruzzi I.,San Raffaele Scientific Institute | Luzi L.,University of Milan | Luzi L.,Metabolism Research Center
Acta Diabetologica | Year: 2017

Abstract: Plethoric evidence reminds of the protective effects of exercise against a number of health risks, across all ages, in the general population. The benefits of exercise for individuals with type 2 diabetes are indisputable. An in-depth understanding of energy metabolism has reasonably entailed exercise as a cornerstone in the lifestyle of almost all subjects with type 1 diabetes. Nevertheless, individuals with type 1 diabetes often fail in accomplishing exercise guidelines and they are less active than their peer without diabetes. Two major obstacles are feared by people with type 1 diabetes who wish to exercise regularly: management of blood glucose control and hypoglycemia. Nowadays, strategies, including glucose monitoring technology and insulin pump therapy, have significantly contributed to the participation in regular physical activity, and even in competitive sports, for people with type 1 diabetes. Novel modalities of training, like different intensity, interspersed exercise, are as well promising. The beneficial potential of exercise in type 1 diabetes is multi-faceted, and it has to be fully exploited because it goes beyond the insulin-mimetic action, possibly through immunomodulation. © 2017 Springer-Verlag Italia


Roveda E.,University of Milan | Vitale J.,IRCCS Instituto Ortopedico Galeazzi | Montaruli A.,University of Milan | Galasso L.,University of Milan | And 3 more authors.
Chronobiology International | Year: 2017

Actigraphy is the reference objective method to measure circadian rhythmicity. One simpler subjective approach to assess the circadian typology is the Morningness–Eveningness Questionnaire (MEQ) by Horne and Ostberg. In this study, we compared the MEQ score against the actigraphy-based circadian parameters MESOR, amplitude and acrophase in a sample of 54 students of the University of Milan in Northern Italy. MEQ and the acrophase resulted strongly and inversely associated (r = −0.84, p < 0.0001), and their relationship exhibited a clear-cut linear trend. We thus used linear regression to develop an equation enabling us to predict the value of the acrophase from the MEQ score. The parameters of the regression model were precisely estimated, with the slope of the regression line being significantly different from 0 (p < 0.0001). The best-fit linear equation was: acrophase (min) = 1238.7–5.49·MEQ, indicating that each additional point in the MEQ score corresponded to a shortening of the acrophase of approximately 5 min. The coefficient of determination, R2, was 0.70. The residuals were evenly distributed and did not show any systematic pattern, thus indicating that the linear model yielded a good, balanced prediction of the acrophase throughout the range of the MEQ score. In particular, the model was able to accurately predict the mean values of the acrophase in the three chronotypes (Morning-, Neither-, and Evening-types) in which the study subjects were categorized. Both the confidence and prediction limits associated to the regression line were calculated, thus providing an assessment of the uncertainty associated with the prediction of the model. In particular, the size of the two-sided prediction limits for the acrophase was about ±100 min in the midrange of the MEQ score. Finally, k-fold cross-validation showed that both the model’s predictive ability on new data and the model’s stability to changes in the data set used for parameter estimation were good. In conclusion, the actigraphy-based acrophase can be predicted using the MEQ score in a population of college students of North Italy. © 2017 Taylor & Francis Group, LLC


Codella R.,University of Milan | Codella R.,Metabolism Research Center | Benedini S.,University of Milan | Benedini S.,Metabolism Research Center | And 13 more authors.
Journal of Diabetes Research | Year: 2017

We investigated the effects of glucose and diverse breakfasts on glucose increment and ghrelin suppression and cognitive processing of sensory information assessed by frontal P300 evoked potentials. In a randomized crossover design, 12 healthy individuals (6M/6F; BMI 22.2 ± 0.4 kg/m2; 27 ± 1.3 years, mean ± SEM) underwent 50 g OGTT (A) and 3 breakfasts (B1: Milk and cereals; B2: Milk, apple, and chocolate cream-filled sponge cake; B3: Milk, apple, bread, and hazelnut chocolate cream) to assess plasma glucose-, insulin-, and ghrelin excursions. An electroencephalography was performed before and 100 min after consumption of each load to measure the latency of frontal P300 evoked potentials as index of cognitive performance. Breakfasts B1 and B2 exhibited significantly lower glycemic and insulinemic responses as compared to A. Breakfast B3 exhibited significantly lower glycemic, but not insulinemic response, as compared to A. Final plasma ghrelin inhibition was more pronounced, albeit not significantly, in all breakfasts with respect to A. P300 latency tended to decrease following each of the three breakfasts, but B3 was the only breakfast capable to elicit a statistically significant reduction in P300 latency with respect to A (p<0.01), suggesting ameliorated cognitive performance. Such amelioration was correlated with the 2-hour final inhibition of plasma ghrelin concentration (r=0.61, p=0.01). © 2017 Roberto Codella et al.


Villa I.,San Raffaele Scientific Institute | Senesi P.,Metabolism Research Center | Montesano A.,University of Milan | Ferraretto A.,Metabolism Research Center | And 9 more authors.
Journal of Translational Medicine | Year: 2017

Background: Betaine (BET), a component of many foods, is an essential osmolyte and a source of methyl groups; it also shows an antioxidant activity. Moreover, BET stimulates muscle differentiation via insulin like growth factor I (IGF-I). The processes of myogenesis and osteogenesis involve common mechanisms with skeletal muscle cells and osteoblasts sharing the same precursor. Therefore, we have hypothesized that BET might be effective on osteoblast cell differentiation. Methods: The effect of BET was tested in human osteoblasts (hObs) derived from trabecular bone samples obtained from waste material of orthopedic surgery. Cells were treated with 10 mM BET at 5, 15, 60 min and 3, 6 and 24 h. The possible effects of BET on hObs differentiation were evaluated by real time PCR, western blot and immunofluorescence analysis. Calcium imaging was used to monitor intracellular calcium changes. Results: Real time PCR results showed that BET stimulated significantly the expression of RUNX2, osterix, bone sialoprotein and osteopontin. Western blot and immunofluorescence confirmed BET stimulation of osteopontin protein synthesis. BET stimulated ERK signaling, key pathway involved in osteoblastogenesis and calcium signaling. BET induced a rise of intracellular calcium by means of the calcium ions influx from the extracellular milieu through the L-type calcium channels and CaMKII signaling activation. A significant rise in IGF-I mRNA at 3 and 6 h and a significant increase of IGF-I protein at 6 and 24 h after BET stimulus was detected. Furthermore, BET was able to increase significantly both SOD2 gene expression and protein content. Conclusions: Our study showed that three signaling pathways, i.e. cytosolic calcium influx, ERK activation and IGF-I production, are enhanced by BET in human osteoblasts. These pathways could have synergistic effects on osteogenic gene expression and protein synthesis, thus potentially leading to enhanced bone formation. Taken together, these results suggest that BET could be a promising nutraceutical therapeutic agent in the strategy to counteract the concomitant and interacting impact of sarcopenia and osteoporosis, i.e. the major determinants of senile frailty and related mortality. © 2017 The Author(s).


PubMed | San Raffaele Scientific Institute, Metabolism Research Center and University of Milan
Type: | Journal: Endocrine | Year: 2016

The purpose of this study is to investigate Ranolazine action on skeletal muscle differentiation and mitochondrial oxidative phenomena. Ranolazine, an antianginal drug, which acts blocking the late INaL current, was shown to lower hemoglobin A1c in patients with diabetes. In the present study, we hypothesized an action of Ranolazine on skeletal muscle cells regeneration and oxidative process, leading to a reduction of insulin resistance.10M Ranolazine was added to C2C12 murine myoblastic cells during proliferation, differentiation and newly formed myotubes.Ranolazine promoted the development of a specific myogenic phenotype: increasing the expression of myogenic regulator factors and inhibiting cell cycle progression factor (p21). Ranolazine stimulated calcium signaling (calmodulin-dependent kinases) and reduced reactive oxygen species levels. Furthermore, Ranolazine maintained mitochondrial homeostasis. During the differentiation phase, Ranolazine promoted myotubes formation. Ranolazine did not modify kinases involved in skeletal muscle differentiation and glucose uptake (extracellular signal-regulated kinases 1/2 and AKT pathways), but activated calcium signaling pathways. During proliferation, Ranolazine did not modify the number of mitochondria while decreasing osteopontin protein levels. Lastly, neo-formed myotubes treated with Ranolazine showed typical hypertrophic phenotype.In conclusion, our results indicate that Ranolazine stimulates myogenesis and reduces a pro-oxidant inflammation/oxidative condition, activating a calcium signaling pathway. These newly described mechanisms may partially explain the glucose lowering effect of the drug.


PubMed | San Raffaele Scientific Institute, Metabolism Research Center, University of Miami and University of Milan
Type: | Journal: Cell transplantation | Year: 2016

Previous studies in humans with type 1 diabetes (T1D) and in non-obese diabetic mice have investigated the beneficial immunomodulatory potential of aerobic physical activity. Performing high volume of aerobic exercise may favorably regulate autoimmunity in diabetes. We tested whether increased physical activity is a self-sufficient positive factor in T1D subjects.

During a 3-month observational period, active (6M; 40.56.1 years; BMI 24.52.1) and sedentary (4M, 3F; 35.98.9 years; BMI 25.73.8) T1D individuals on insulin pump therapy were studied for metabolic, inflammatory and autoimmune parameters. At baseline and at the end of a 3-month period, glycosylated hemoglobin (HbA1c), auto-antibodies (anti-GAD, anti-ZnT8, anti-IA2, ICA) and pro-inflammatory cytokines (IL-6 and TNF-) were evaluated. During the 3rd month of the period, physically active T1D patients showed a significant reduction in the average glucose levels (-9%, p=0.025, by CGM) compared to the 1st-month values, and even their hyperglycemic episodes (>180mg/dL) diminished significantly (-24.2%, p=0.032 vs 1st month). Moreover, active T1D subjects exhibited an improved body composition with respect to sedentary controls. No significant changes were detected as to the autoimmune and inflammatory profiles.

This study confirms the beneficial role of physical exercise associated with insulin pump therapy in order to improve metabolic control in individuals with T1D. These preliminary positive observations need to be challenged in a prolonged interventional follow-up.


PubMed | Metabolism Research Center, Endocrinology Unit and University of Milan
Type: | Journal: Case reports in endocrinology | Year: 2015

Type 1 diabetes mellitus (T1D), autoimmune thyroid disease, and autoimmune gastritis often occur together forming the so-called autoimmune polyendocrine syndrome type 3 (APS3). We here report a clinical case of a 74-year-old woman who presented for the first time with severe hyperglycemia and ketoacidosis diagnosed as T1D. Further clinical investigations revealed concomitant severe hypothyroidism with autoimmune thyroid disease and severe cobalamin deficiency due to chronic atrophic gastritis. The diagnosis of type 1 diabetes mellitus was confirmed by the detection of autoantibodies against glutamic acid decarboxylase 65, islet cell antibodies, and anti-insulin autoantibodies. Anti-thyroperoxidase, anti-thyroglobulin, and anti-gastric parietal cell antibodies were also clearly positive. The case emphasized that new onset diabetic ketoacidosis, hypothyroidism, and cobalamin deficiency may simultaneously occur, and one disease can mask the features of the other, thereby making diagnosis difficult. It is noteworthy that an APS3 acute episode occurred in an asymptomatic elder woman for any autoimmune diseases.


Formenti D.,University of Milan | Ludwig N.,University of Milan | Trecroci A.,University of Milan | Gargano M.,University of Milan | And 4 more authors.
Journal of Thermal Biology | Year: 2016

Low intensity resistance training with slow movement and tonic force generation has been shown to create blood flow restriction within muscles that may affect thermoregulation through the skin. We aimed to investigate the influence of two speeds of exercise execution on skin temperature dynamics using infrared thermography. Thirteen active males performed randomly two sessions of squat exercise (normal speed, 1 s eccentric/1 s concentric phase, 1 s; slow speed, 5 s eccentric/5 s concentric phase, 5 s), using ~50% of 1 maximal repetition. Thermal images of ST above muscles quadriceps were recorded at a rate of 0.05 Hz before the exercise (to determine basal ST) and for 480 s following the initiation of the exercise (to determine the nonsteady-state time course of ST). Results showed that ST changed more slowly during the 5 s exercise (p=0.002), whereas the delta (with respect to basal) excursions were similar for the two exercises (p>0.05). In summary, our data provided a detailed nonsteady-state portrait of ST changes following squat exercises executed at two different speeds. These results lay the basis for further investigations entailing the joint use of infrared thermography and Doppler flowmetry to study the events taking place both at the skin and the muscle level during exercises executed at slow speed. © 2016 Elsevier Ltd.

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