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Obesity is a condition that generally limits work capacity and predisposes to a number of comorbidities and related diseases, the last being COVID-19 and its complications and sequelae. Physical exercise, together with diet, is a milestone in its management and rehabilitation, although there is still a debate on intensity and duration of training. Anaerobic threshold (AT) is a broad term often used either as ventilatory threshold or as lactate threshold, respectively, detected by respiratory ventilation and/or respiratory gases (VCO 2 and VO 2 ), and by blood lactic acid. This review outlines the role of AT and of the different variations of growth hormone and catecholamine, in subjects with obesity vs normal weight individuals below and beyond AT, during a progressive increase in exercise training. We present a re-evaluation of the effects of physical activity on body mass and metabolism of individuals with obesity in light of potential benefits and pitfalls during COVID-19 pandemic. Comparison of a training program at moderate-intensity exercise (< AT) with training performed at moderate intensity (< AT) plus a final bout of high-intensity (> AT) exercise at the end of the aerobic session will be discussed. Based on our data and considerations, a tailored strategy for individuals with obesity concerning the most appropriate intensity of training in the context of rehabilitation is proposed, with special regard to potential benefits of work program above AT. Adding bouts of exercise above AT may improve lactic acid and H + disposal and improve growth hormone. Long-term aerobic exercise may improve leptin reduction. In this way, the propensity of subjects with obesity to encounter a serious prognosis of COVID-19 may be counteracted and the systemic and cardiorespiratory sequelae that may ensue after COVID-19, can be overcome. Individuals with serious comorbidities associated with obesity should avoid excessive exercise intensity.

BACKGROUND:Professional, long-term physical training is often associated with morphological and metabolic changes in the heart. This study was undertaken to assess the left ventricular (LV) and right ventricular (RV) morphology and function and the LV high-energy phosphates of athletes trained to a sustained power or aerobic exercise.METHODS:Magnetic resonance imaging (MRI) of the LV and RV and phosphorous 31 magnetic resonance spectroscopy of the LV were performed by means of a 1.5-T clinical scanner in 23 elite track sprinters (sustained power or anaerobic power sprint training, 100-400 m) or marathon runners (sustained aerobic endurance training) and in 10 sedentary, young, lean men.RESULTS:Athletes had LV hypertrophy and unaffected chamber size, systolic and diastolic functions, and high-energy phosphates metabolism. Also, the RV of the athletes was hypertrophied in comparison with that of the nonathletic controls, and the systolic and diastolic functions were unaffected; the chamber volume was higher in the sprinters (end-diastolic volume 190 +/- 15 mL) in comparison with that of the marathon runners (174 +/- 19 mL, P < .05) and controls (168 +/- 19 mL, P < .01) even if this difference, when adjusted for body surface area, was maintained only when compared with that of controls (P < .02).CONCLUSIONS:Left ventricular and RV hypertrophy in athletes is associated with normal systolic and diastolic functions and resting cardiac energy metabolism, supporting its benign nature. A more pronounced RV dilatation was found in the anaerobic power athletes and further investigation is warranted to establish the clinical significance of this training effect.

Myotonic distrophy (MyD), the most common adult form of muscular dystrophy, is often complicated by diabetes. MyD is dominantly inherited and is due to heterozygosity for a tri-nucleotide repeat expansion mutation in a protein kinase gene which was suggested to induce derangement of RNA metabolism able to reduce insulin receptor expression. To test whether the abnormal RNA metabolism or a specific malfunction of protein kinase gene induces defective energy metabolism and insuline resistance prior to the onset of diabetes, we studied 10 MyD patients (2 glucose intolerant) and 10 matched healthy subjects, by means of (a) dual X-ray energy absorption, (b) euglycemic-hyperinsulinemic clamp ( 1 mU/Kg/min) combined with primed-continuous infusion of [6,6-d2]-glucose and [1-13C]-leucine, (c) indirect calorimetry, and (d) oral glucose tolerance test (OGTT) to explore insulin-dependent glucose, lipid and protein metabolism. MyD reduced Jean body mass (LBM: 36 ± 3 vs 46 ± 3 Kg; P < 0.02) and increased fat mass. Nevertheless, resting energy expenditure (33.4 ± 0.9 vs 33.8 ± 1.5 kcal/kg/day; P = 0.83), insulin-stimulated glucose metabolism [7.22 ± 0.22 vs 8.48 ± 0.80 mg/(kg LBM · min); P = 0.49], and lipid metabolism in the postabsortive and clamp conditions were comparable to normals. Proinsulin concentrations were increased in MyD patients (P = 0.01) and the intact proinsulin/insulin ratio (23 ± 4 vs 10 ± 1%; P < 0.01) was twofold higher in MyD. Circulating proinsulin levels also failed to be normally regulated during suppressing (clamp) or stimulating (OGTT) conditions. Markers of proteolysis (ELF: endogenous leucine flux) in the postabsorptive [203 ± 15 vs 146 ± 9 μmol/(kg LBM · h); P < 0.02] and insulin-stimulated conditions (ELF suppression during the insulin clamp: 11 ± 3 vs 18 ± 2%; P < 0.05) were higher in MyD than in normals and they were associated to reduced plasma insulin-like growth factor (IGF-1: 125 ± 18 vs 212 ± 8 ng/ml; P < 0.03) and increased plasma α-tumor necrosis factor receptor-2 (TNFR-2: 1919 ± 212 vs 1401 ± 172 pg/ml, P = 0.04). In summary, in MyD, energy metabolism was preserved but the severe loss of LBM was associated with abnormal postabsorptive and insulin-stimulated regulation of protein breakdown. Insulin resistance with respect to glucose metabolism was lacking, and a higher risk to develop type 2 diabetes is more likely due to abnormal insulin secretion. The combination of reduced circulating IGF-1 levels and increased TNF system activity may be responsible for the increased protein breakdown which is involved in muscle wasting in MyD

Successful intraportal islet transplantation normalizes glucose metabolism in diabetic humans. To date, full function is not routinely achieved after islet transplantation in humans, with most grafts being characterized by only partial function. Moreover, the duration of full function is variable and cannot be sufficiently predicted with available methods. In contrast, most grafts retain partial function for a long time. We hypothesized that partial function can restore normal protein and lipid metabolism in diabetic individuals. We studied 45 diabetic patients after islet transplantation. Labeled glucose and leucine were infused to assess whole-body glucose and protein turnover in 1) 6 type 1 diabetic patients with full function after intraportal islet transplantation (FF group; C-peptide > 0.6 nmol/l; daily insulin dosage 0.03 +/- 0.02 U x kg(-1) body wt x day(-1); fasting plasma glucose < 7.7 mmol/l; HbA1c < or = 6.5%), 2) 17 patients with partial function (PF group; C-peptide > 0.16 nmol/l; insulin dosage < 0.4 U x kg(-1) body wt x day(-1)), 3) 9 patients with no function (NF group; C-peptide < 0.16 nmol/l; insulin dosage > 0.4 U x kg(-1) body wt x day(-1)), and 4) 6 patients with chronic uveitis as control subjects (CU group). Hepatic albumin synthesis was assessed in an additional five PF and five healthy volunteers by means of a primed-continuous infusion of [3,3,3-2H3]leucine. The insulin requirement was 97% lower than pretransplant levels for the FF group and 57% lower than pretransplant levels for the PF group. In the basal state, the PF group had a plasma glucose concentration slightly higher than that of the FF (P = 0.249) and CU groups (P = 0.08), but was improved with respect to the NF group (P < 0.01). Plasma leucine (101.1 +/- 5.9 micromol/l) and branched-chain amino acids (337.6 +/- 16.6 micromol/l) were similar in the PF, FF, and CU groups, and significantly lower than in the NF group (P < 0.01). During insulin infusion, the metabolic clearance rate of glucose was defective in the NF group versus in the other groups (P < 0.01). Both the basal and insulin-stimulated proteolytic and proteosynthetic rates were comparable in the PF, FF, and CU groups, but significantly higher in the NF group (P = 0.05). In addition, the PF group had a normal hepatic albumin synthesis. Plasma free fatty acid concentrations in the PF and FF groups were similar to those of the CU group, but the NF group showed a reduced insulin-dependent suppression during the clamp. We concluded that the restoration of approximately 60% of endogenous insulin secretion is capable of normalizing the alterations of protein and lipid metabolism in type 1 diabetic kidney recipients, notwithstanding chronic immunosuppressive therapy. The results of the present study indicate that "success" of islet transplantation may be best defined by a number of metabolic criteria, not just glucose concentration/metabolism alone.

Total acquired lipoatrophic diabetes (LD) is characterized by muscle mass hypertrophy, non-ketotic hyperglycaemia and insulin resistance with respect to glucose and lipid metabolism. To assess whether the defect in insulin action extends to leucine/protein metabolism, a female subject (age=33 years; body weight=44 kg; HbAlc=9.5%) with LD was studied twice: in study I we used a three-step euglycaemic hyperinsulinaemic clamp (40, 80 and 200 mU · m-2 · min-1) combined with [3-3H]glucose and [1-14C]leucine infusions along with indirect calorimetry. In study II we used a 40 mU · m-2 · min-1 euglycaemic hyperaminoacidaemic (plasma leucine 160 μmol/l) hyperinsulinaemic clamp. Five controls were also studieD. In the basal state the patient with LD had plasma leucine (130 μmol/l), isoleucine (63), valine (169) and phenylalanine levels (48) comparable to those of the controls. Basal hepatic glucose production (3.2 vs 2.0±0.2 mg · kg-1 · min-1), endogenous leucine flux (ELF=45.4 vs 40±1 μmol · m-2 · min-1) and non-oxidative leucine disposal (NOLD=37.2 vs 34±1 μmol · m-2 · min-1) were increased in the patient with LD, while basal leucine oxidation (LO=8.2 vs 6.0±2 μmol · m-2 · min-1) was similar in LD and controls. Following the three-step insulin infusion, insulin-stimulated glucose metabolism was defective in the subject with LD (glucose oxidation=60%, 50%, and 52% of controls; non-oxidative glucose disposal =39%, 34% and 30% of controls at 40, 80 and 200 mU · m-2 · min-1 respectively). The decrease of leucine, isoleucine, valine and phenylalanine, as well as the suppression of ELF, LO and NOLD was defective in the subject with LD at each insulin step. In vitro studies demonstrated a defect in receptor insulin binding on erythrocytes, the absence of anti-insulin receptor antibodies and the presence of insulin antibodies in the serum of the patient with LD. Following combined hyperaminoacidaemia/hyperinsulinaemia a similar stimulation of protein synthetic rate (20 vs 30%) was demonstrated in the patient with LD and controls respectively. In conclusion the patient with LD shows a reduced insulin sensitivity and a reduced maximal response to insulin in both glucose and protein metabolism. The present data support the hypothesis that in LD the defect in insulin action is both at the receptor and post-receptorial sites. The patient with LD showed a normal stimulation of protein synthesis under combined hyperinsulinaemic/hyperaminoacidaemic conditions. Our results may explain the muscle mass hypertrophy in LD. © 1992 Springer-Verlag

Background: Professional, long-term physical training is often associated with morphological and metabolic changes in the heart. This study was undertaken to assess the left ventricular (LV) and right ventricular (RV) morphology and function and the LV high-energy phosphates of athletes trained to a sustained power or aerobic exercise. Methods: Magnetic resonance imaging (MRI) of the LV and RV and phosphorous 31 magnetic resonance spectroscopy of the LV were performed by means of a 1.5-T clinical scanner in 23 elite track sprinters (sustained power or anaerobic power sprint training, 100-400 m) or marathon runners (sustained aerobic endurance training) and in 10 sedentary, young, lean men. Results: Athletes had LV hypertrophy and unaffected chamber size, systolic and diastolic functions, and high-energy phosphates metabolism. Also, the RV of the athletes was hypertrophied in comparison with that of the nonathletic controls, and the systolic and diastolic functions were unaffected; the chamber volume was higher in the sprinters (end-diastolic volume 190 ± 15 mL) in comparison with that of the marathon runners (174 ± 19 mL, P < .05) and controls (168 ± 19 mL, P < .01) even if this difference, when adjusted for body surface area, was maintained only when compared with that of controls (P < .02). Conclusions: Left ventricular and RV hypertrophy in athletes is associated with normal systolic and diastolic functions and resting cardiac energy metabolism, supporting its benign nature. A more pronounced RV dilatation was found in the anaerobic power athletes and further investigation is warranted to establish the clinical significance of this training effect. © 2007 Mosby, Inc. All rights reserved

OBJECTIVE—Fatty liver may be involved in the pathogenesis of type 2 diabetes. Physical exercise is a tool to improve insulin sensitivity, but little is known about its effect on intrahepatic fat (IHF) content. The purpose of this study was to examine the association of habitual physical activity, insulin resistance, and adiponectin with IHF content. RESEARCH DESIGN AND METHODS—Participants were 191 (77 female and 114 male) apparently healthy, nonalcoholic individuals (aged 19–62 years; BMI 17.0–35.5 kg/m2). IHF content was assessed in a quantitative fashion and noninvasively as a continuous variable by means of 1H magnetic resonance spectroscopy (MRS), and habitual physical activity was assessed by means of a questionnaire. Fatty liver was defined as IHF content of >5% wet weight, and insulin sensitivity was estimated using the computer homeostasis model assessment (HOMA)-2 indexes. RESULTS—A reduced prevalence of fatty liver in the quartile of the most physically active individuals (25, 11, 25, and 2% in quartile 1, 2, 3, and 4, respectively; χ2 = 15.63; P = 0.001) was found along with an inverse correlation between the physical activity index and the IHF content when plotted as continuous variables (Pearson’s r = −0.27; P < 0.000). This association was not attenuated when adjusted for age, sex, BMI, HOMA-2, and adiponectin (partial correlation r = −0.25; P < 0.001). CONCLUSIONS—This study demonstrated that a higher level of habitual physical activity is associated with a lower IHF content and suggested that this relationship may be due to the effect of exercise per se.

Aims/hypothesis: Resistin is an adipokine associated with obesity and type 2 diabetes in animal models, but in humans its role remains uncertain. This study was undertaken to test whether serum resistin is related to insulin resistance and markers of low-grade inflammation in elite athletes taken as a model of extreme insulin sensitivity. Subjects materials and methods: In 23 elite athletes (sprinters, middle-distance and marathon runners) and in 72 sedentary men including lean and obese individuals with NGT, and obese individuals with IGT or new-onset type 2 diabetes, we assessed insulin sensitivity using a whole-body insulin-sensitivity index (WBISI) derived from a 3-h OGTT; energy homeostasis was also assessed by means of indirect calorimetry, along with circulating adipokines and low-grade pro-inflammatory cyto-chemokines. Results: Professional athletes had increased WBISIs (p

To assess the effect of pancreas transplantation on free fatty acid (FFA) and glucose metabolism, we studied seven uremic IDDM patients (HbA1c 9.1%), nine IDDM patients after combined kidney-pancreas transplantation (HbA1c 5.8%), seven patients with chronic uveitis (HbA1c 5.6%), and nine normal control subjects (HbA1c 5.5%) by means of the [3-3H]glucose and [1-14C]palmitate infusion techniques combined with indirect calorimetry and euglycemic insulin clamp. In the postabsorptive state, pancreas-transplant patients had similar plasma glucose and FFA concentrations and non-statistically different rates of hepatic glucose production (HGP) and FFA turnover, while demonstrating a reduced rate of FFA oxidation (42 ± 5 vs. 73 ± 10 μmicromol · m−2 · min−1; P < 0.05) compared with control subjects. After 180 min of tracer equilibration, all subjects underwent a low-dose (100 min, 8 mU · m−2 · min−1) followed by a high-dose (100 min, 40 mU · m−2 · min−1) euglycemic insulin infusion. During insulin infusion, pancreas-transplant patients showed a greater inhibition of FFA concentration (609 ± 76 to 58 ± 15 micromol/l) compared with healthy subjects (681 ± 90 to 187 ± 25 micromol/l; P < 0.01 vs. pancreas-transplant patients). FFA turnover and oxidation rates during both low-dose and high-dose insulin infusions were lower in pancreas-transplant patients compared with healthy subjects (P < 0.03 and P < 0.01, for turnover and oxidation, respectively). Uremic IDDM patients demonstration altered basal and insulin-mediated glucose metabolism. Pancreas transplantation normalized only insulin-mediated glucose oxidation, leaving the stimulation of non-oxidative glucose disposal still markedly defective. In conclusion, patients after pancreas transplantation have normal basal FFA turnover and reduced basal FFA oxidation rates. During hyperinsulinemia, pancreas-transplant patients show a normal inhibition of FFA turnover and FFA oxidation. Insulin-mediated glucose metabolism remained abnormal after pancreas transplantation. Our findings may be related to the effect of chronic immunosuppressive therapy on glucose and FFA metabolism.

The ability of chronic endogenous hyperinsulinemia to induce a resistance to insulin action on protein and glucose metabolism was studied in 10 subjects affected by a benign (functioning) insulinoma and 18 healthy subjects by means of infusions of [l-14C]leucine and [3-3H] glucose. The insulinoma subjects were divided into two groups with moderate (139 ± 12 pmol/1) (n = 5) and marked (438 ± 42 pmol/1) (n = 5) hyperinsulinemia and were studied during a euglycemic dextrose infusion. Control subjects were studied postabsorptively and during a low-dose (0.3 mU · kg−1·min−1) (n = 3) and a high-dose (1 mU · kg−1 · min−1) (n = 15) euglycemic insulin clamp to match peripheral insulin concentrations with those of insulinoma subjects. In insulinoma subjects there was no correlation among plasma insulin concentration and leucine concentration (r = 0.05), endogenous leucine flux (r = 0.44), hepatic glucose production (r = 0.47), and glucose uptake (r = 0.05). Insulinoma subjects with marked hyperinsulinemia demonstrated a defective suppression of leucine concentrations (100 ± 11 vs. 65 ± 5 μmol/l,P < 0.01), endogenous leucine flux (50.1 ± 6.3 vs. 27.1 ± 0.9 μmol · m−2 · min−1, P < 0.01), and hepatic glucose production (5.4 ± 2.0 vs. 0.6 ± 0.6 ± mol · kg−1 · min−1, P < 0.05), and a defective stimulation of glucose uptake (13.5 ± 1.6 vs. 41.1 ± 2.8 ± mol · kg−1 · min−1, P

The intraportal injection of human pancreatic islets has been indicated as a possible alternative to the pancreas transplant in insulin-dependent diabetic patients. Aim of the present work was to study the effect of intraportal injection of purified human islets on: (a) the basal hepatic glucose production; (b) the whole body glucose homeostasis and insulin action; and (c) the regulation of insulin secretion in insulin-dependent diabetes mellitus patients bearing a kidney transplant. 15 recipients of purified islets from cadaver donors (intraportal injection) were studied by means of the infusion of labeled glucose to quantify the hepatic glucose production. Islet transplanted patients were subdivided in two groups based on graft function and underwent: (a) a 120-min euglycemic insulin infusion (1 mU/kg/min) to assess insulin action; (b) a 120-min glucose infusion (+75 mg/di) to study the pattern of insulin secretion. Seven patients with chronic uveitis on the same immunosuppressive therapy as grafted patients, twelve healthy volunteers, and seven insulin-dependent diabetic patients with combined pancreas and kidney transplantation were also studied as control groups. Islet transplanted patients have: (a) a higher basal hepatic glucose production (HGP: 5.1 +/- 1.4 mg/kg/ min; P < 0.05 with respect to all other groups) if without graft function, and a normal HGP (2.4 +/- 0.2 mg/kg/min) with a functioning graft; (b) a defective tissue glucose disposal (3.9 +/- 0.5 mg/kg/min in patients without islet function and 5.3 +/- 0.4 mg/kg/min in patients with islet function) with respect to normals (P < 0.01 for both comparisons); (c) a blunted first phase insulin peak and a similar second phase secretion with respect to controls. In conclusion, in spite of the persistence of an abnormal pattern of insulin secretion, successful intraportal islet graft normalizes the basal HGP and improves total tissue glucose disposal in insulin-dependent diabetes mellitus.

The liver plays a major role in regulating glucose metabolism, and since its function is influenced by sympathetic/ parasympathetic innervation, we used liver graft as a model of denervation to study the role of CNS in modulating hepatic glucose metabolism in humans. 22 liver transplant subjects were randomly studied by means of the hyperglycemic/ hyperinsulinemic (study 1), hyperglycemic/isoinsulinemic (study 2), euglycemic/hyperinsulinemic (study 3) as well as insulin-induced hypoglycemic (study 4) clamp, combined with bolus-continuous infusion of [3-3H]glucose and indirect calorimetry to determine the effect of different glycemic/insulinemic levels on endogenous glucose production and on peripheral glucose uptake. In addition, postabsorptive glucose homeostasis was cross-sectionally related to the transplant age (range = 40 d-35 mo) in 4 subgroups of patients 2, 6, 15, and 28 mo after transplantation. 22 subjects with chronic uveitis (CU) undergoing a similar immunosuppressive therapy and 35 normal healthy subjects served as controls. The results showed that successful transplantation was associated with fasting glucose concentration and endogenous glucose production in the lower physiological range within a few weeks after transplantation, and this pattern was maintained throughout the 28-mo follow-up period. Fasting glucose (4. 55+/-0.06 vs. 4.75+/-0.06 mM; P = 0.038) and endogenous glucose production (11.3+/-0.4 vs. 12.9+/-0.5 micromol/[kg.min]; P = 0.029) were lower when compared to CU and normal patients. At different combinations of glycemic/insulinemic levels, liver transplant (LTx) patients showed a comparable inhibition of endogenous glucose production. In contrast, in hypoglycemia, after a temporary fall endogenous glucose production rose to values comparable to those of the basal condition in CU and normal subjects (83+/-5 and 92+/-5% of basal), but it did not in LTx subjects (66+/-7%; P < 0.05 vs. CU and normal subjects). Fasting insulin and C-peptide levels were increased up to 6 mo after transplantation, indicating insulin resistance partially induced by prednisone. In addition, greater C-peptide but similar insulin levels during the hyperglycemic clamp (study 1) suggested an increased hepatic insulin clearance in LTx as compared to normal subjects. Fasting glucagon concentration was higher 6 mo after transplantation and thereafter. During euglycemia/hyperinsulinemia (study 3), the insulin-induced glucagon suppression detectable in CU and normal subjects was lacking in LTx subjects; furthermore, the counterregulatory response during hypoglycemia was blunted. In summary, liver transplant subjects have normal postabsorptive glucose metabolism, and glucose and insulin challenge elicit normal response at both hepatic and peripheral sites. Nevertheless, (a) minimal alteration of endogenous glucose production, (b) increased concentration of insulin and glucagon, and (c) defective counterregulation during hypoglycemia may reflect an alteration of the liver-CNS-islet circuit which is due to denervation of the transplanted graft.