Pharmacological modulation of adaptive thermogenesis: new clues for obesity management?

BACKGROUND: Adaptive thermogenesis represents the main mechanism through which the body generates heat in response to external stimuli, a phenomenon that includes shivering and non-shivering thermogenesis. The non-shivering thermogenesis is mainly exploited by adipose tissue characterized by a brown aspect, which specializes in energy dissipation. A decreased amount of brown adipose tissue has been observed in ageing and chronic illnesses such as obesity, a worldwide health problem characterized by dysfunctional adipose tissue expansion and associated cardiometabolic complications. In the last decades, the discovery of a trans-differentiation mechanism ("browning") within white adipose tissue depots, leading to the generation of brown-like cells, allowed to explore new natural and synthetic compounds able to favour this process and thus enhance thermogenesis with the aim of counteracting obesity. Based on recent findings, brown adipose tissue-activating agents could represent another option in addition to appetite inhibitors and inhibitors of nutrient absorption for obesity treatment. PURPOSE: This review investigates the main molecules involved in the physiological (e.g. incretin hormones) and pharmacological (e.g. ß3-adrenergic receptors agonists, thyroid receptor agonists, farnesoid X receptor agonists, glucagon-like peptide-1, and glucagon receptor agonists) modulation of adaptive thermogenesis and the signalling mechanisms involved.

Noradrenergic fibers are associated with beta-cell dedifferentiation and impaired beta-cell function in humans.

AIMS/HYPOTHESIS: Type 2 diabetes (T2D) is characterized by a progressive loss of beta-cell function, and the "disappearance" of beta-cells in T2D may also be caused by the process of beta -cell dedifferentiation. Since noradrenergic innervation inhibits insulin secretion and density of noradrenergic fibers is increased in type 2 diabetes mouse models, we aimed to study the relation between islet innervation, dedifferentiation and beta-cell function in humans. METHODS: Using immunohistochemistry and electron microscopy, we analyzed pancreata from organ donors and from patients undergoing pancreatic surgery. In the latter, a pre-surgical detailed metabolic characterization by oral glucose tolerance test (OGTT) and hyperglycemic clamp was performed before surgery, thus obtaining in vivo functional parameters of beta-cell function and insulin secretion. RESULTS: The islets of diabetic subjects were 3 times more innervated than controls (0.91 ±â€¯0.21 vs 0.32 ±â€¯0.10, n.fibers/islet; p = 0.01), and directly correlated with the dedifferentiation score (r = 0.39; p = 0.03). In vivo functional parameters of insulin secretion, assessed by hyperglycemic clamp, negatively correlated with the increase in fibers [beta-cell Glucose Sensitivity (r = -0.84; p = 0.01), incremental second-phase insulin secretion (r = -0.84, p = 0.03) and arginine-stimulated insulin secretion (r = -0.76, p = 0.04)]. Moreover, we observed a progressive increase in fibers, paralleling worsening glucose tolerance (from NGT through IGT to T2D). CONCLUSIONS/INTERPRETATION: Noradrenergic fibers are significantly increased in the islets of diabetic subjects and this positively correlates with beta-cell dedifferentiation score. The correlation between in vivo insulin secretion parameters and the density of pancreatic noradrenergic fibers suggests a significant involvement of these fibers in the pathogenesis of the disease, and indirectly, in the islet dedifferentiation process.

Vitamin D deficiency: a new risk factor for type 2 diabetes?.

Recent compelling evidence suggests a role of vitamin D deficiency in the pathogenesis of insulin resistance and insulin secretion derangements, with a consequent possible interference with type 2 diabetes mellitus. The mechanism of this link is incompletely understood. In fact, vitamin D deficiency is usually detected in obesity in which insulin resistance is also a common finding. The coexistence of insulin resistance and vitamin D deficiency has generated several hypotheses. Some cross-sectional and prospective studies have suggested that vitamin D deficiency may play a role in worsening insulin resistance; others have identified obesity as a risk factor predisposing individuals to exhibit both vitamin D deficiency and insulin resistance. The available data from intervention studies are largely confounded, and inadequate considerations of seasonal effects on 25(OH)D concentrations are also a common design flaw in many studies. On the contrary, there is strong evidence that obesity might cause both vitamin D deficiency and insulin resistance, leaving open the possibility that vitamin D and diabetes are not related at all. Although it might seem premature to draw firm conclusions on the role of vitamin D supplementation in reducing insulin resistance and preventing type 2 diabetes, this manuscript will review the circumstances leading to vitamin D deficiency and how such a deficiency can eventually independently affect insulin sensitivity.

Metabolic syndrome in transplant patients: an updating point of view.

Metabolic syndrome (MS) is a cluster of risk factors that predispose to major cardiovascular diseases and its complications, determining liver and kidney impairment. In the last decade, the indications to transplantation are increasing, with a linear incidence of the complications of the procedure. MS represents one of the commonest, being in turn may the consequence of the underlying disease that required the transplantation, or the result of the medical treatment, as well as one of the most important factor influencing the morbidity and mortality of the transplanted patients. Due to the growing incidence of the MS in these patients, it is crucial to focus and clarify the leading causes determining the onset of the metabolic disarrangement, its outcome and the hypothetical mechanism through which the clinicians could reduce the impact of the disease. In fact, prevention, early recognition, and treatment of the factor that could predict the onset or progression of the MS after the transplantation may impact long term survival of patients, that is again the scope of the same transplant. This review will update the different mechanisMS of the pathogenesis of MS in this population, the clinical effects of the presence of the MS, observing the risk factors to be treated before and after the transplantation and suggesting the management of the follow-up.

Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives.

Several studies have shown that vitamin D may play a role in many biochemical mechanisms in addition to bone and calcium metabolism. Recently, vitamin D has sparked widespread interest because of its involvement in the homeostasis of the cardiovascular system. Hypovitaminosis D has been associated with obesity, related to trapping in adipose tissue due to its lipophilic structure. In addition, vitamin D deficiency is associated with increased risk of cardiovascular disease (CVD) and this may be due to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which it might modulate cardiovascular risk are not fully understood. Given this background, in this work we summarise clinical retrospective and prospective observational studies linking vitamin D levels with cardio-metabolic risk factors and vascular outcome. Moreover, we review various randomised controlled trials (RCTs) investigating the effects of vitamin D supplementation on surrogate markers of cardiovascular risk. Considering the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D replacement therapy in this population may be warranted; however, further RCTs are urgently needed to establish when to begin vitamin D therapy, as well as to determine the dose and route and duration of administration.

Critical role of chemokine (C-C motif) receptor 2 (CCR2) in the KKAy + Apoe -/- mouse model of the metabolic syndrome.

AIMS/HYPOTHESIS: Chemokines and their receptors such as chemokine (C-C motif) receptor 2 (CCR2) may contribute to the pathogenesis of the metabolic syndrome via their effects on inflammatory monocytes. Increased accumulation of CCR2-driven inflammatory monocytes in epididymal fat pads is thought to favour the development of insulin resistance. Ultimately, the resulting hyperglycaemia and dyslipidaemia contribute to development of the metabolic syndrome complications such as cardiovascular disease and diabetic nephropathy. Our goal was to elucidate the role of CCR2 and inflammatory monocytes in a mouse model that resembles the human metabolic syndrome. METHODS: We generated a model of the metabolic syndrome by backcrossing KKAy ( + ) with Apoe ( -/- ) mice (KKAy ( + ) Apoe ( -/- )) and studied the role of CCR2 in this model system. RESULTS: KKAy ( + ) Apoe ( -/- ) mice were characterised by the presence of obesity, insulin resistance, dyslipidaemia and increased systemic inflammation. This model also manifested two complications of the metabolic syndrome: atherosclerosis and diabetic nephropathy. Inactivation of Ccr2 in KKAy (+) Apoe ( -/- ) mice protected against the metabolic syndrome, as well as atherosclerosis and diabetic nephropathy. This protective phenotype was associated with a reduced number of inflammatory monocytes in the liver and muscle, but not in the epididymal fat pads; circulating levels of adipokines such as leptin, resistin and adiponectin were also not reduced. Interestingly, the proportion of inflammatory monocytes in the liver, pancreas and muscle, but not in the epididymal fat pads, correlated significantly with peripheral glucose levels. CONCLUSIONS/INTERPRETATION: CCR2-driven inflammatory monocyte accumulation in the liver and muscle may be a critical pathogenic factor in the development of the metabolic syndrome.

In anorexia nervosa, even a small increase in abdominal fat is responsible for the appearance of insulin resistance.

CONTEXT: The aim of treatment in patients affected by anorexia nervosa (AN) is weight recovery. However, during weight gain, anorectic patients' body composition is changed, with an increase in abdominal fat, particularly in the visceral compartment. OBJECTIVE: We hypothesized that changes in body composition, particularly in abdominal fat, are responsible for the variability in insulin sensitivity (IS) in different stages of AN. DESIGN AND MEASUREMENTS: We compared 20 anorectic patients in the acute stage, 19 in the weight-recovery stage and 21 controls. All subjects underwent an oral glucose tolerance test, hyperinsulinaemic euglycaemic clamp and dual energy X-ray absorptiometry to measure body composition. RESULTS: The percentage of trunk fat was higher in weight recovery than in the acute phase (47·7 ± 8·4%vs 34·6 ± 7·6%; P ≤ 0·01) and in the control group (33·4 ± 7·6; P < 0·01 vs weight recovery). Although the recovery group gained weight, their body mass index (BMI) was not statistically different from that of the acute group (14·4 ± 1·1 vs 13·6 ± 1·8 kg/m(2) ). Insulin sensitivity was lower in the weight-recovery group than the acute group (4·7 ± 1·5 vs 7·8 ± 1·6 mg/kg/min; P < 0·01) and controls (7·7 ± 1·4 mg/kg/min; P < 0·01). A linear negative correlation was found between IS and the percentage of abdominal fat in the weight-recovery and acute groups (r = -0·51; P = 0·04 and r = -0·53; P = 0·04 respectively), while IS did not correlate with BMI. CONCLUSION: Although weight-recovery represents the main aim of treatment in AN, refeeding is associated with an increase in abdominal fat which might be responsible of the onset of insulin resistance. As BMI and weight-recovery were associated with impaired IS, they cannot be considered the only aim of treatment of AN.

Metabolic syndrome in transplant patients: an academic or a health burden?

Metabolic syndrome is a cluster of risk factors that predispose to major cardiovascular diseases, liver steatosis and fibrosis, as well as reduced renal function. Metabolic syndrome and its early hepatic manifestation, non-alcoholic fatty liver disease, are prevalent both among the general population and in pre- and posttransplantation settings. Because indications for solid-organ transplantation are gradually increasing, attention should focus on the incidence of metabolic syndrome among transplanted patients, defined as posttransplant metabolic syndrome (PTMS). Subjects with worse metabolic profiles with two or more criteria of the syndrome show lower survival rates and greater co-morbidities. However, it is still unclear whether the pathophysiology of posttransplantation metabolic syndrome differ from that of the general population and may be determined by the primary disease affecting the liver or kidney, or amplified or altered by the immunosuppressive treatment, as it has already been established that corticosteroids and calcineurin inhibitors cause metabolic disarrangements. Although there is controversy regarding the definition and the impact of PTMS on overall survival rates following transplantation, these patients are at increased risk for cardiovascular morbidity and mortality. Early recognition, prevention, and treatment of these conditions may impact long-term survival after transplantation. Thus, even if metabolic syndrome in transplant patients remains an unclear definition, an insulin resistance is present in these patients. The treatment of this condition represents a health problem that requires intervention by clinicians before and after transplantation.

Glucose toxicity: the leading actor in the pathogenesis and clinical history of type 2 diabetes - mechanisms and potentials for treatment.

AIM: Although it is now well established that the deleterious effects of chronic hyperglycaemia (i.e., glucose toxicity) play an important role in the progressive impairment of insulin secretion and sensitivity, the two major actors of the pathogenesis of type 2 diabetes mellitus, the precise biochemical and molecular mechanisms responsible for the defects induced by glucose toxicity still remain to be defined. DATA SYNTHESIS: here we will briefly report on convincing evidence that glucose toxicity acts through oxidative stress, modifications in the exosamine pathway, protein kinase C and others. After inducing or contributing to the genesis of type 2 diabetes, these same mechanisms are considered responsible for the appearance and worsening of diabetic specific microvascular complications, while its role in increasing the risk of cardiovascular diseases is less clear. Recent intervention studies (ADVANCE, ACCORD, VADT), conducted to evaluate the effects of strict glycaemic control, apparently failed to demonstrate an effect of glucose toxicity on cardiovascular diseases, at least in secondary prevention or when diabetes is present for a prolonged time. The re-examination, 20 years later, of the population studied in the UKPDS study, however, clearly demonstrated that the earliest is the strict glycaemic control reached, the lowest is the incidence of cardiovascular diseases observed, including myocardial infarction. CONCLUSION: The acquaintance of the role of glucose toxicity should strongly influence the usual therapeutic choices and glycaemic targets where the reduced or absent risk of hypoglycaemia, durability of action, and data on prolonged safety should be the preferred characteristics of the drug of choice in the treatment of type 2 diabetes mellitus.

[In situ ductal carcinoma of the breast: current status and our experience]. / Il carcinoma duttale in situ della mammella: situazione attuale e nostra esperienza.

INTRODUCTION: Selecting the appropriate treatment strategy for the individual patient with DCIS represents a major challenge to the surgeon treating breast cancer in the 1990's. CASES AND METHODS: In this study 48 "pure" DCIS patients, treated at Surgical Department of Genoa University, have been selected and divided into Van Nuys prognostic groups. New prognostic classification (Van Nuys) defines three distinct and easily recognizable groups, each of which has a different likelihood of local recurrence if treated with breast conservation. RESULTS: Our results confirm that the risk of local recurrence increases in close relation with prognostic classification groups and suggests that different forms of DCIS may require different treatments.

Timing of surgery related to menstrual cycle and prognosis of premenopausal women with breast cancer.

The influence of the timing of surgery in relation to the menstrual cycle on the survival of breast cancer patients has been both advocated and disputed. The records of 165 premenopausal M- breast cancer women consecutively operated from 1977 to 1991 were reviewed. All patients underwent modified radical mastectomies or quadrantectomies plus postoperative radiotherapy. Node-positive patients received adjuvant chemotherapy. Cox regression analysis was used to estimate the relative risk (RR) of death in three models including timing of surgery, age, histology, pT and pN. In each model, patients were divided into two groups according to the criteria proposed by Badwe, Hrushesky, and Senie. Multivariate analysis showed a significant association between pT and pN and survival, whereas no association with survival was observed for the timing of surgery according to either Badwe or Hrushesky or Senie (RR = 1.26, RR = 0.91 and RR = 0.88 respectively). Consensus on the menstrual phase related to the expected best prognosis is still required.

High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule.

The optimal use of mitoxantrone (NOV) in the high-dose range requires elucidation of its maximum tolerated dose with peripheral blood progenitor cell (PBPC) support and the time interval needed between drug administration and PBPC reinfusion in order to avoid graft toxicity. The aims of this study were: (1) to verify the feasibility and haematological toxicity of escalating NOV up to 90 mg m(-2) with PBPC support; and (2) to verify the safeness of a short (96 h) interval between NOV administration and PBPC reinfusion. Three cohorts of ten patients with breast cancer (BC) or non-Hodgkin's lymphoma (NHL) received escalating doses of NOV, 60, 75 and 90 mg m(-2) plus melphalan (L-PAM), 140-180 mg m(-2), with PBPC rescue 96 h after NOV. Haematological toxicity was evaluated daily (WHO criteria). NOV plasma pharmacokinetics was also evaluated, as well as NOV cytotoxicity against PBPCs. Haematological recovery was rapid and complete at each NOV dose level without statistically significant differences, and there were no major toxicities. NOV plasma concentrations at the time of PBPC reinfusion were below the toxicity threshold against haemopoietic progenitors. It is concluded that, when adequately supported with PBPCs, NOV can be escalated up to 90 mg m(-2) with acceptable haematological toxicity. PBPCs can be safely reinfused as early as 96 h after NOV administration.

[Radiotherapy and breast cancer. A review of the literature]. / Radioterapia e cancro della mammella. Una revisione di letteratura.

Breast cancer is the commonest neoplastic disease in women; radiotherapy is frequently used in patients with breast cancer. In the past decade, most attention has been devoted to conservative treatment of early (Stage I-II) breast cancer. Informations derived from the literature, about results, cosmesis, risk of relapse, and the various problems of combining radiotherapy with different surgical approaches and with chemotherapy, are presented and discussed. Recent data about post mastectomy irradiation and treatment of locoregional relapses, and about the role of radiotherapy in treating locally advanced and inflammatory breast cancer, are also presented and discussed.

[Treatment of breast carcinoma. Our experience]. / Il trattamento del carcinoma della mammella. Nostra esperienza.

The results of a study on 848 patients with breast carcinoma having maximum diameter less than or equal to 2 cm, that underwent a surgical treatment at the Institute of Special Surgical Pathology B (1980-82) and at the Institute of Surgical Clinic I (1980-89) are presented. The study has the purpose of evaluating, by the analysis of ten years surviving curves, the effectiveness of different types of interventions: Halsted radical mastectomy (98 patients), Patey radical mastectomy (245 patients) and Madden radical mastectomy (151 patients), quadrantectomy (260 patients). The age of patients ranges from 29 years to 92 years (average 56 years). The 68.04% of all tumors have resulted invasive ductal carcinoma (NOS) the 9.08% lobular carcinoma. Of the 848 patients included in the study 698 are alive at the end of the follow-up, with a survival rate, calculated with the actuarial method, equivalent to 63.38%. Results show the survival is independent of the type of surgical treatment (71.9% for quadrantectomy; 70.7% for Halsted radical mastectomy, 68.9% for Patey radical mastectomy; 70.7% for Madden radical mastectomy).(ABSTRACT TRUNCATED AT 250 WORDS)

[Reconstruction of the breast: critical evaluation of surgical technics]. / La ricostruzione della mammella: valutazione critica delle tecniche chirurgiche.

After reviewing the reasons for the increasingly widespread practice of breast reconstruction, the authors describe at some length the most reliable surgical techniques available and, on the basis of the results obtained, suggest an even broader range of indications for this type of surgical therapy.

Delayed development and rupture of an aortic aneurysm after closed abdominal trauma.

A case is reported of a patient who, following the surgical repair of a lesion of the superior mesenteric artery secondary to a closed abdominal trauma, slowly developed an aneurysm of the abdominal aorta which subsequently ruptured. Surgical management of the aneurysm by aortic graft implantation proved successful.