Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreaticβcells,insulin resistance in peripheral tissues,or both,and resu...Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreaticβcells,insulin resistance in peripheral tissues,or both,and results in a non-sufficient production of insulin.To adjust blood glucose levels,diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity.With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities,different strategies have been investigated.The first approaches included enhancing endogenousβcell activity or transplanting new islets.The protocol for this kind of intervention has recently been optimized,leading to standardized procedures.It is indicated for diabetic patients with severe hypoglycemia,complicated by impaired hypoglycemia awareness or exacerbated glycemic lability.Transplantation has been associated with improvement in all comorbidities associated with diabetes,quality of life,and survival.However,different trials are ongoing to further improve the beneficial effects of transplantation.Furthermore,to overcome some limitations associated with the availability of islets/pancreas,alternative therapeutic strategies are under evaluation,such as the use of mesenchymal stem cells(MSCs)or induced pluripotent stem cells for transplantation.The cotransplantation of MSCs with islets has been successful,thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms,including exosome release.The use of induced pluripotent stem cells is recent and requires further investigation.The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities,such as wound healing.Despite the number of advantages of the direct injection of MSCs,new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results.In conclusion,this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.展开更多
Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research.Although the onset of these two diseases can occur in a different way,recent studies h...Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research.Although the onset of these two diseases can occur in a different way,recent studies have shown that obesity and osteoporosis share common genetic and environmental factors.Despite being a risk factor for health,obesity has traditionally been considered positive to bone because of beneficial effect of mechanical loading,exerted by high body mass,on bone formation.However,contrasting studies have not achieved a clear consensus,suggesting instead that excessive fat mass derived from obesity condition may not protect against osteoporosis or,even worse,could be rather detrimental to bone.On the other hand,it is hitherto better established that,since adipocytes and osteoblasts are derived from a common mesenchymal stem cell precursor,molecules that lead to osteoblastogenesis inhibit adipogenesis and vice versa.Here we will discuss the role of the key molecules regulating adipocytes and osteoblasts differentiation,which are peroxisome proliferators activated receptor-γand Wnts,respectively.In particular,wewill focus on the role of both canonical and non-canonical Wnt signalling,involved in mesenchymal cell fate regulation.Moreover,at present there are no experimental data that relate any influence of the Wnt inhibitor Sclerostin to adipogenesis,although it is well known its role on bone metabolism.In addition,the most common pathological condition in which there is a simultaneous increase of adiposity and decrease of bone mass is menopause.Given that postmenopausal women have high Sclerostin level inversely associated with circulating estradiol level and since the sex hormone replacement therapy has proved to be effective in attenuating bone loss and reversing menopause-related obesity,we hypothesize that Sclerostin contribution in adipogenesis could be an active focus of research in the coming years.展开更多
Bone loss associated with type 1 diabetes mellitus(T1DM)begins at the onset of the disease,already in childhood,determining a lower bone mass peak and hence a greater risk of osteoporosis and fractures later in life.T...Bone loss associated with type 1 diabetes mellitus(T1DM)begins at the onset of the disease,already in childhood,determining a lower bone mass peak and hence a greater risk of osteoporosis and fractures later in life.The mechanisms underlying diabetic bone fragility are not yet completely understood.Hyperglycemia and insulin deficiency can affect the bone cells functions,as well as the bone marrow fat,thus impairing the bone strength,geometry,and microarchitecture.Several factors,like insulin and growth hormone/insulin-like growth factor 1,can control bone marrow mesenchymal stem cell commitment,and the receptor activator of nuclear factor-κB ligand/osteoprotegerin and Wnt-b catenin pathways can impair bone turnover.Some myokines may have a key role in regulating metabolic control and improving bone mass in T1DM subjects.The aim of this review is to provide an overview of the current knowledge of the mechanisms underlying altered bone remodeling in children affected by T1DM.展开更多
Type 2 diabetes(T2D)is a global epidemic disease.The prevalence of T2D in adolescents and young adults is increasing alarmingly.The mechanisms leading to T2D in young people are similar to those in older patients.Howe...Type 2 diabetes(T2D)is a global epidemic disease.The prevalence of T2D in adolescents and young adults is increasing alarmingly.The mechanisms leading to T2D in young people are similar to those in older patients.However,the severity of onset,reduced insulin sensitivity and defective insulin secretion can be different in subjects who develop the disease at a younger age.T2D is associated with different complications,including bone fragility with consequent susceptibility to fractures.The purpose of this systematic review was to describe T2D bone fragility together with all the possible involved pathways.Numerous studies have reported that patients with T2D show preserved,or even increased,bone mineral density compared with controls.This apparent paradox can be explained by the altered bone quality with increased cortical bone porosity and compromised mechanical properties.Furthermore,reduced bone turnover has been described in T2D with reduced markers of bone formation and resorption.These findings prompted different researchers to highlight the mechanisms leading to bone fragility,and numerous critical altered pathways have been identified and studied.In detail,we focused our attention on the role of microvascular disease,advanced glycation end products,the senescence pathway,the Wnt/β-catenin pathway,the osteoprotegerin/receptor-activator of nuclear factor kappa B ligand,osteonectin and fibroblast growth factor 23.The understanding of type 2 myeloid bone fragility is an important issue as it could suggest possible interventions for the prevention of poor bone quality in T2D and/or how to target these pathways when bone disease is clearly evident.展开更多
Background Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs),the bone-reabsorbing cells,and osteoblasts (OBs),and the bone-forming cells.This equilibrium is regulated by numerous ...Background Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs),the bone-reabsorbing cells,and osteoblasts (OBs),and the bone-forming cells.This equilibrium is regulated by numerous cytokines,but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis,respectively.The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1).RANKL,sclerostin and DKKs-1 are often up-regulated in bone diseases,and they are the target of new monoclonal antibodies.Data sources The authors performed a systematic literature search in PubMed and EMBASE to June 2018,reviewed and selected articles,based on pre-determined selection criteria.Results We re-evaluated the role of RANKL,osteoprotegerin,sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases,such as type 1 diabetes mellitus (T1DM),alkaptonuria (AKU),hemophilia A,osteogenesis imperfecta (OI),21-hydroxylase deficiency (21 OH-D) and Prader-Willi syndrome (PWS).To do so,we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-β-catenin signaling pathways have been investigated,and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed.Conclusions The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases.Furthermore,for some of them,bone damage began in childhood but only manifested with age.The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children,although further studies need to be carried out.展开更多
文摘Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreaticβcells,insulin resistance in peripheral tissues,or both,and results in a non-sufficient production of insulin.To adjust blood glucose levels,diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity.With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities,different strategies have been investigated.The first approaches included enhancing endogenousβcell activity or transplanting new islets.The protocol for this kind of intervention has recently been optimized,leading to standardized procedures.It is indicated for diabetic patients with severe hypoglycemia,complicated by impaired hypoglycemia awareness or exacerbated glycemic lability.Transplantation has been associated with improvement in all comorbidities associated with diabetes,quality of life,and survival.However,different trials are ongoing to further improve the beneficial effects of transplantation.Furthermore,to overcome some limitations associated with the availability of islets/pancreas,alternative therapeutic strategies are under evaluation,such as the use of mesenchymal stem cells(MSCs)or induced pluripotent stem cells for transplantation.The cotransplantation of MSCs with islets has been successful,thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms,including exosome release.The use of induced pluripotent stem cells is recent and requires further investigation.The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities,such as wound healing.Despite the number of advantages of the direct injection of MSCs,new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results.In conclusion,this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.
文摘Studies concerning the pathophysiological connection between obesity and osteoporosis are currently an intriguing area of research.Although the onset of these two diseases can occur in a different way,recent studies have shown that obesity and osteoporosis share common genetic and environmental factors.Despite being a risk factor for health,obesity has traditionally been considered positive to bone because of beneficial effect of mechanical loading,exerted by high body mass,on bone formation.However,contrasting studies have not achieved a clear consensus,suggesting instead that excessive fat mass derived from obesity condition may not protect against osteoporosis or,even worse,could be rather detrimental to bone.On the other hand,it is hitherto better established that,since adipocytes and osteoblasts are derived from a common mesenchymal stem cell precursor,molecules that lead to osteoblastogenesis inhibit adipogenesis and vice versa.Here we will discuss the role of the key molecules regulating adipocytes and osteoblasts differentiation,which are peroxisome proliferators activated receptor-γand Wnts,respectively.In particular,wewill focus on the role of both canonical and non-canonical Wnt signalling,involved in mesenchymal cell fate regulation.Moreover,at present there are no experimental data that relate any influence of the Wnt inhibitor Sclerostin to adipogenesis,although it is well known its role on bone metabolism.In addition,the most common pathological condition in which there is a simultaneous increase of adiposity and decrease of bone mass is menopause.Given that postmenopausal women have high Sclerostin level inversely associated with circulating estradiol level and since the sex hormone replacement therapy has proved to be effective in attenuating bone loss and reversing menopause-related obesity,we hypothesize that Sclerostin contribution in adipogenesis could be an active focus of research in the coming years.
文摘Bone loss associated with type 1 diabetes mellitus(T1DM)begins at the onset of the disease,already in childhood,determining a lower bone mass peak and hence a greater risk of osteoporosis and fractures later in life.The mechanisms underlying diabetic bone fragility are not yet completely understood.Hyperglycemia and insulin deficiency can affect the bone cells functions,as well as the bone marrow fat,thus impairing the bone strength,geometry,and microarchitecture.Several factors,like insulin and growth hormone/insulin-like growth factor 1,can control bone marrow mesenchymal stem cell commitment,and the receptor activator of nuclear factor-κB ligand/osteoprotegerin and Wnt-b catenin pathways can impair bone turnover.Some myokines may have a key role in regulating metabolic control and improving bone mass in T1DM subjects.The aim of this review is to provide an overview of the current knowledge of the mechanisms underlying altered bone remodeling in children affected by T1DM.
文摘Type 2 diabetes(T2D)is a global epidemic disease.The prevalence of T2D in adolescents and young adults is increasing alarmingly.The mechanisms leading to T2D in young people are similar to those in older patients.However,the severity of onset,reduced insulin sensitivity and defective insulin secretion can be different in subjects who develop the disease at a younger age.T2D is associated with different complications,including bone fragility with consequent susceptibility to fractures.The purpose of this systematic review was to describe T2D bone fragility together with all the possible involved pathways.Numerous studies have reported that patients with T2D show preserved,or even increased,bone mineral density compared with controls.This apparent paradox can be explained by the altered bone quality with increased cortical bone porosity and compromised mechanical properties.Furthermore,reduced bone turnover has been described in T2D with reduced markers of bone formation and resorption.These findings prompted different researchers to highlight the mechanisms leading to bone fragility,and numerous critical altered pathways have been identified and studied.In detail,we focused our attention on the role of microvascular disease,advanced glycation end products,the senescence pathway,the Wnt/β-catenin pathway,the osteoprotegerin/receptor-activator of nuclear factor kappa B ligand,osteonectin and fibroblast growth factor 23.The understanding of type 2 myeloid bone fragility is an important issue as it could suggest possible interventions for the prevention of poor bone quality in T2D and/or how to target these pathways when bone disease is clearly evident.
文摘Background Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs),the bone-reabsorbing cells,and osteoblasts (OBs),and the bone-forming cells.This equilibrium is regulated by numerous cytokines,but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/β-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis,respectively.The pro-osteoblastogenic activity of the Wnt/β-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1).RANKL,sclerostin and DKKs-1 are often up-regulated in bone diseases,and they are the target of new monoclonal antibodies.Data sources The authors performed a systematic literature search in PubMed and EMBASE to June 2018,reviewed and selected articles,based on pre-determined selection criteria.Results We re-evaluated the role of RANKL,osteoprotegerin,sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases,such as type 1 diabetes mellitus (T1DM),alkaptonuria (AKU),hemophilia A,osteogenesis imperfecta (OI),21-hydroxylase deficiency (21 OH-D) and Prader-Willi syndrome (PWS).To do so,we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-β-catenin signaling pathways have been investigated,and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed.Conclusions The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases.Furthermore,for some of them,bone damage began in childhood but only manifested with age.The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children,although further studies need to be carried out.
