RESUMO
The physiological role of immune cells in the regulation of postprandial glucose metabolism has not been fully elucidated. We have found that adipose tissue macrophages produce interleukin-10 (IL-10) upon feeding, which suppresses hepatic glucose production in cooperation with insulin. Both elevated insulin and gut-microbiome-derived lipopolysaccharide in response to feeding are required for IL-10 production via the Akt/mammalian target of rapamycin (mTOR) pathway. Indeed, myeloid-specific knockout of the insulin receptor or bone marrow transplantation of mutant TLR4 marrow cells results in increased expression of gluconeogenic genes and impaired glucose tolerance. Furthermore, myeloid-specific Akt1 and Akt2 knockout results in similar phenotypes that are rescued by additional knockout of TSC2, an inhibitor of mTOR. In obesity, IL-10 production is impaired due to insulin resistance in macrophages, whereas adenovirus-mediated expression of IL-10 ameliorates postprandial hyperglycemia. Thus, the orchestrated response of the endogenous hormone and gut environment to feeding is a key regulator of postprandial glycemia.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Hiperglicemia/patologia , Insulina/farmacologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/análise , Gluconeogênese/genética , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina , Interleucina-10/fisiologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Período Pós-Prandial , Transdução de Sinais , Serina-Treonina Quinases TOR/genética , Proteína 2 do Complexo Esclerose Tuberosa/fisiologiaRESUMO
Sarcopenia is distinct from normal muscle atrophy in that it is closely related to a shift in the muscle fiber type. Deficiency of the anabolic action of androgen on skeletal muscles is associated with sarcopenia; however, the function of the androgen receptor (AR) pathway in sarcopenia remains poorly understood. We generated a mouse model (fast-twitch muscle-specific AR knockout [fmARKO] mice) in which the AR was selectively deleted in the fast-twitch muscle fibers. In young male mice, the deletion caused no change in muscle mass, but it reduced muscle strength and fatigue resistance and induced a shift in the soleus muscles from fast-twitch fibers to slow-twitch fibers (14% increase, P = 0.02). After middle age, with the control mice, the male fmARKO mice showed much less muscle function, accompanied by lower hindlimb muscle mass; this phenotype was similar to the progression of sarcopenia. The bone mineral density of the femur was significantly reduced in the fmARKO mice, indicating possible osteosarcopenia. Microarray and gene ontology analyses revealed that in male fmARKO mice, there was downregulation of polyamine biosynthesis-related geneswhich was confirmed by liquid chromatography-tandem mass spectrometry assay and the primary cultured myofibers. None of the AR deletion-related phenotypes were observed in female fmARKO mice. Our findings showed that the AR pathway had essential muscle type- and sex-specific roles in the differentiation toward fast-twitch fibers and in the maintenance of muscle composition and function. The AR in fast-twitch muscles was the dominant regulator of muscle fiber-type composition and muscle function, including the muscle-bone relationship.
Assuntos
Doenças Musculares , Sarcopenia , Camundongos , Masculino , Feminino , Animais , Sarcopenia/genética , Sarcopenia/metabolismo , Receptores Androgênicos/metabolismo , Fibras Musculares de Contração Lenta/metabolismo , Músculo Esquelético/metabolismo , Fibras Musculares de Contração Rápida/metabolismo , Doenças Musculares/metabolismo , Fenótipo , Camundongos KnockoutRESUMO
Insulin is a hormone that positively regulates anabolism and cell growth, whereas diabetes mellitus is a disease characterized by hyperglycemia associated with impaired insulin action. My colleagues and I have elucidated multifaceted insulin action in various tissues mainly by means of model mice. In the liver, insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis comorbid with diabetes. Not only the liver but also the proximal tubules of the kidney are important in the regulation of gluconeogenesis, and we revealed that insulin suppresses gluconeogenesis in accordance with absorbed glucose in the latter tissue. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease of skeletal muscle, but also to osteopenia and shorter longevity. Aging is regulated by adipokines as well, and it should be considered that aging could be accelerated by 'imbalanced adipokines' in patients with a genetic background of progeria. Moreover, we reported the effects of intensive multifactorial intervention on diabetic vascular complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, and the results of subsequent sub-analyses of renal events and fracture events. Various approaches of research enable us of endocrinologists to elucidate the physiology of hormone signaling, the mechanisms underlying the development of endocrine diseases, and the appropriate treatment measures. These approaches also raise fundamental questions, but addressing them in an appropriate manner will surely contribute to the further development of endocrinology.
Assuntos
Diabetes Mellitus Tipo 2 , Insulina , Humanos , Animais , Insulina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/terapia , Estresse do Retículo Endoplasmático/fisiologia , Transdução de Sinais , Músculo Esquelético/metabolismo , Fígado/metabolismo , Hipoglicemiantes/uso terapêutico , Envelhecimento/fisiologia , Envelhecimento/metabolismo , Resistência à Insulina/fisiologia , Camundongos , Gluconeogênese/fisiologiaRESUMO
Although growing evidence supports the benefits of glucagon-like peptide-1 receptor agonists, the renoprotective effects were not fully proven in clinical trials. Now, Xu et al. show that glucagon-like peptide-1 receptor agonists reduce the renal outcome compared with dipeptidyl peptidase-4 inhibitors in a retrospective cohort study of the participants in the Stockholm Creatinine Measurements project undertaken in Stockholm, Sweden. Despite some limitations, the study shows renoprotection by glucagon-like peptide-1 receptor agonists and raises hope about upcoming evidence from prospective clinical trials.
Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Humanos , Hipoglicemiantes/uso terapêutico , Estudos Prospectivos , Estudos RetrospectivosRESUMO
To evaluate the effect of multifactorial intervention on the onset and progression of diabetic kidney disease in the patients with type 2 diabetes, we analyzed the effects of intensified multifactorial intervention by step-wise intensification of medications and life-style modifications (intensive therapy treatment targets; HbA1c under 6.2%, blood pressure under 120/75 mmHg, low-density lipoprotein cholesterol under 80 mg/dL) comparing with the guideline-based standard care (conventional therapy treatment targets: HbA1c under 6.9%, blood pressure under 130/80 mmHg, low-density lipoprotein cholesterol under 120 mg/dL) on diabetic kidney disease. A total of 2540 eligible patients in the Japan Diabetes Optimal Integrated Treatment for three major risk factors of cardiovascular diseases (J-DOIT3) cohort were randomly assigned to intensive therapy (1269) and conventional therapy (1271) and treated for a median of 8.5 years. The prespecified kidney outcome measure was a composite of progression from normoalbuminuria to microalbuminuria or progression from normoalbuminuria to macroalbuminuria or progression from microalbuminuria to macroalbuminuria, serum creatinine levels elevated by two-fold or more compared to baseline, or kidney failure. Primary analysis was carried out on the intention-to-treat population. Changes in the estimated glomerular filtration rate and albuminuria were also analyzed. A total of 438 kidney events occurred (181 in the intensive therapy group and 257 in the conventional therapy group). Intensive therapy was associated with a significant 32% reduction in kidney events compared to conventional therapy and was associated with a change in HbA1c at one year from study initiation. Thus, prespecified analysis shows that intensified multifactorial intervention significantly reduced the onset and progression of diabetic kidney disease compared to currently recommended care.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Albuminúria/epidemiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/terapia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/etiologia , Taxa de Filtração Glomerular , Humanos , JapãoRESUMO
Among the tissues involved in the motor system, skeletal muscle plays an important role in systemic metabolism and is the largest organ in terms of glucose uptake. Insulin promotes anabolism of nutrients in skeletal muscle, as in other insulin-targeted organs, and maintains muscle volume, in cooperation with insulin-like growth factor-1. In humans, along with aging, insulin resistance is induced in skeletal muscle, which could lead to systemic insulin resistance, and circulating IGF-1 levels are lowered. These changes contribute to the development of sarcopenia, in which function and volume of skeletal muscle are impaired, and modulation of the insulin/IGF-1 signaling could be promising in treatment of sarcopenia.
Assuntos
Homeostase , Atividade Motora , Doenças Musculoesqueléticas/metabolismo , Envelhecimento , Humanos , Insulina/metabolismo , Músculo Esquelético/metabolismo , Transdução de SinaisRESUMO
Insulin and IGF-1 share many of the downstream molecules involved in the signal transduction, and cooperatively maintain volume of skeletal muscle. Along with aging, however, insulin/IGF-1 signaling is impaired, mainly due to insulin resistance and lowered IGF-1 levels, which is thought to promote the development of sarcopenia, and thus they are among the promising therapeutic targets. It is also known that sarcopenia is associated with the development of frailty, one of the phenomena of systemic aging. Actually insulin/IGF-1 signaling is known to affect longevity in lower organisms, but in humans, little is known about roles of the signaling in the development of frailty, and further investigation is needed.
Assuntos
Fragilidade , Sarcopenia , Envelhecimento , Humanos , Insulina , Fator de Crescimento Insulin-Like I , Músculo Esquelético , Transdução de SinaisRESUMO
Insulin and IGF-1 have a high similarity in structure and play pivotal roles in regulation of aging and longevity. Insulin is bound to insulin receptor on cell surface, whereas IGF-1 is bound to IGF1R, but the molecules to transduce intracellular signals are almost identical, including Akt and FoxO. Akt is a kinase to regulate growth and metabolism in various tissues, and among the substrates, FoxO is one of the key transcription factors to regulate expression of a number or genes, including anti-oxidative enzymes. Akt phosphorylates FoxO and sup- presses its activity by promoting translocation to cytoplasm. In yeast, worms and flies, it is known that various mutations to impair insulin/IGF-1 signaling prolong longevity, potentially via activation of FoxO. In mice, however, longevity was prolonged in some models with disrup- tion of insulin/IGF-1 signaling-related genes, whereas it was shortened in others. Moreover, in many cases, prolonged longevity was accompanied by growth retardation or metabolic disorders, which means that they did not live a 'long and healthy' life. It is still controversial whether suppression of insulin/IGF-1 signaling is beneficial in terms of aging also in mammalians.
Assuntos
Envelhecimento , Fator de Crescimento Insulin-Like I , Insulina , Transdução de Sinais , Envelhecimento/fisiologia , Animais , Humanos , Insulina/fisiologia , Fator de Crescimento Insulin-Like I/fisiologia , Longevidade/fisiologiaRESUMO
Obesity and insulin resistance, the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation characterized by abnormal macrophage infiltration into adipose tissues. Although it has been reported that chemokines promote leukocyte migration by activating class IB phosphoinositide-3 kinase (PI3Kγ) in inflammatory states, little is known about the role of PI3Kγ in obesity-induced macrophage infiltration into tissues, systemic inflammation, and the development of insulin resistance. In the present study, we used murine models of both diet-induced and genetically induced obesity to examine the role of PI3Kγ in the accumulation of tissue macrophages and the development of obesity-induced insulin resistance. Mice lacking p110γ (Pik3cg(-/-)), the catalytic subunit of PI3Kγ, exhibited improved systemic insulin sensitivity with enhanced insulin signaling in the tissues of obese animals. In adipose tissues and livers of obese Pik3cg(-/-) mice, the numbers of infiltrated proinflammatory macrophages were markedly reduced, leading to suppression of inflammatory reactions in these tissues. Furthermore, bone marrow-specific deletion and pharmacological blockade of PI3Kγ also ameliorated obesity-induced macrophage infiltration and insulin resistance. These data suggest that PI3Kγ plays a crucial role in the development of both obesity-induced inflammation and systemic insulin resistance and that PI3Kγ can be a therapeutic target for type 2 diabetes.
Assuntos
Inflamação/tratamento farmacológico , Resistência à Insulina , Obesidade/complicações , Inibidores de Fosfoinositídeo-3 Quinase , Tecido Adiposo/citologia , Animais , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Citometria de Fluxo , Perfilação da Expressão Gênica , Técnicas Histológicas , Inflamação/etiologia , Fígado/citologia , Macrófagos/fisiologia , Camundongos , Camundongos Knockout , Quinoxalinas/farmacologia , Tiazolidinedionas/farmacologiaRESUMO
It is important to prevent not only diabetic complications but also diabetic comorbidities in diabetes care. We have elucidated multifaceted insulin action in various tissues mainly by means of model mice, and it was revealed that insulin regulates endoplasmic reticulum (ER) stress response during feeding, whereas ER stress 'response failure' contributes to the development of steatohepatitis, one of the major diabetic comorbidities. Insulin regulates gluconeogenesis not only in the liver but also in the proximal tubules of the kidney, which is also suppressed by reabsorbed glucose in the latter. In skeletal muscle, another important insulin-targeted tissue, impaired insulin/IGF-1 signaling leads not only to sarcopenia, an aging-related disease, but also to bone loss and shorter longevity. Aging is regulated by adipokines as well, and it is deemed to be accelerated by 'imbalanced adipokines' in combination with genetic background of progeria. Moreover, we reported effects of intensive multifactorial intervention on diabetic complications and mortality in patients with type 2 diabetes in a large-scale clinical trial, the J-DOIT3, followed by reports of subsequent sub-analyses of renal events and fracture events. Various approaches to elucidate the mechanisms underlying the development of diabetes and how it should be treated are expected to help us improve diabetes management.
RESUMO
CONTEXT: Trinucleotide repeats in the androgen receptor have been proposed to influence testosterone signaling in men, but the clinical relevance of these trinucleotide repeats remains controversial. OBJECTIVE: To examine how androgen receptor trinucleotide repeat lengths affect androgen-related traits and disease risks and whether they influence the clinical importance of circulating testosterone levels. METHODS: We quantified CAG and GGC repeat lengths in the androgen receptor (AR) gene of European-ancestry male participants in UK Biobank from whole-genome and whole-exome sequence data using ExpansionHunter, and tested associations with androgen-related traits and diseases. We also examined whether the associations between testosterone levels and these outcomes were affected by adjustment for the repeat lengths. RESULTS: We successfully quantified the repeat lengths from whole-genome and/or whole-exome sequence data in 181,217 males. Both repeat lengths were shown to be positively associated with circulating total testosterone level and bone mineral density, whereas CAG repeat length was negatively associated with male-pattern baldness, but their effects were relatively small and were not associated with most of the other outcomes. Circulating total testosterone level was associated with various outcomes, but this relationship was not affected by adjustment for the repeat lengths. CONCLUSION: In this large-scale study, we found that longer CAG and GGC repeats in the AR gene influence androgen resistance, elevate circulating testosterone level via a feedback loop and play a role in some androgen-targeted tissues. Generally, however, circulating testosterone level is a more important determinant of androgen action in males than repeat lengths.
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A novel algorithm, AlphaMissense, has been shown to have an improved ability to predict the pathogenicity of rare missense genetic variants. However, it is not known whether AlphaMissense improves the ability of gene-based testing to identify disease-influencing genes. Using whole-exome sequencing data from the UK Biobank, we compared gene-based association analysis strategies including sets of deleterious variants: predicted loss-of-function (pLoF) variants only, pLoF plus AlphaMissense pathogenic variants, pLoF with missense variants predicted to be deleterious by any of five commonly utilized annotation methods (Missense (1/5)) or only variants predicted to be deleterious by all five methods (Missense (5/5)). We measured performance to identify 519 previously identified positive control genes, which can lead to Mendelian diseases, or are the targets of successfully developed medicines. These strategies identified 850k pLoF variants and 5 million deleterious missense variants, including 22k likely pathogenic missense variants identified exclusively by AlphaMissense. The gene-based association tests found 608 significant gene associations (at P<1.25x10-7) across 24 common traits and diseases. Compared to pLoFs plus Missense (5/5), tests using pLoFs and AlphaMissense variants found slightly more significant gene-disease and gene-trait associations, albeit with a marginally lower proportion of positive control genes. Nevertheless, their overall performance was similar. Merging AlphaMissense with Missense (5/5), whether through their intersection or union, did not yield any further enhancement in performance. In summary, employing AlphaMissense to select deleterious variants for gene-based testing did not improve the ability to identify genes that are known to influence disease.
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The potential liability to hypercatabolism in lipodystrophy remains to be fully elucidated. Here we report a 28-year-old Japanese woman with acquired generalized lipodystrophy, who presented with recurrence of panniculitis and anemia. After corticosteroid treatment was started, she showed rapid reductions in body weight and lean mass by 15% at maximum, accompanied by an elevated urea nitrogen/creatinine ratio, which recovered almost fully as the corticosteroid treatment was tapered and discontinued. She had multiple risk factors for hypercatabolism: lack of metabolic reserves, insulin resistance, and hyperglycemia due to lipodystrophy, lowered daily activity due to anemia, persistent inflammation, and wasting associated with panniculitis, and relatively insufficient energy and protein intake during hospitalization. More attention should be paid to the potential liability to hypercatabolism in patients with lipodystrophy, and to skeletal muscle loss as an adverse effect of corticosteroid treatment in patients at high risk, such as those with diabetes or decreased metabolic reserves.
Assuntos
Lipodistrofia , Músculo Esquelético , Humanos , Feminino , Adulto , Lipodistrofia/induzido quimicamente , Lipodistrofia/complicações , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêuticoRESUMO
Genome-wide association studies have identified several gene polymorphisms, including UBE2E2, associated with type 2 diabetes. Although UBE2E2 is one of the ubiquitin-conjugating enzymes involved in the process of ubiquitin modifications, the pathophysiological roles of UBE2E2 in metabolic dysfunction are not yet understood. Here, we showed upregulated UBE2E2 expression in the islets of a mouse model of diet-induced obesity. The diabetes risk allele of UBE2E2 (rs13094957) in noncoding regions was associated with upregulation of UBE2E2 mRNA in the human pancreas. Although glucose-stimulated insulin secretion was intact in the isolated islets, pancreatic ß-cell-specific UBE2E2-transgenic (TG) mice exhibited reduced insulin secretion and decreased ß-cell mass. In TG mice, suppressed proliferation of ß-cells before the weaning period and while receiving a high-fat diet was accompanied by elevated gene expression levels of p21, resulting in decreased postnatal ß-cell mass expansion and compensatory ß-cell hyperplasia, respectively. In TG islets, proteomic analysis identified enhanced formation of various types of polyubiquitin chains, accompanied by increased expression of Nedd4 E3 ubiquitin protein ligase. Ubiquitination assays showed that UBE2E2 mediated the elongation of ubiquitin chains by Nedd4. The data suggest that UBE2E2-mediated ubiquitin modifications in ß-cells play an important role in regulating glucose homeostasis and ß-cell mass.
Assuntos
Diabetes Mellitus Tipo 2 , Intolerância à Glucose , Células Secretoras de Insulina , Camundongos , Animais , Humanos , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Estudo de Associação Genômica Ampla , Proteômica , Células Secretoras de Insulina/metabolismo , Glucose/metabolismo , Camundongos Transgênicos , Dieta Hiperlipídica/efeitos adversos , Ubiquitinas/genética , Ubiquitinas/metabolismo , Insulina/metabolismoRESUMO
The goal of diabetes management is to achieve longevity and quality of life equivalent to those of people without diabetes, and for that, it is now deemed important to pay close attention not only to diabetic vascular complications but also to diabetic comorbidities, as is recommended by the Japan Diabetes Society. In this editorial, we focus on sarcopenia as an important diabetic comorbidity which is an aging-related phenomenon in skeletal muscle. Taking our recent report on a sarcopenia mouse model and other accumulated evidence into account, we propose the existence of a skeletal muscle-centered inter-tissue network that regulates frailty and systemic aging. Sarcopenia is deemed to be a state in which skeletal muscle serving as a protective mighty armor against frailty and systemic aging is lost, and it is vitally important to establish how to recover it and keep it in good shape, so that the goal of diabetes management can be achieved.
Assuntos
Fragilidade , Sarcopenia , Animais , Camundongos , Idoso , Humanos , Sarcopenia/etiologia , Fragilidade/complicações , Qualidade de Vida , Idoso Fragilizado , Envelhecimento/fisiologia , Músculo EsqueléticoRESUMO
In the management of diabetes mellitus, one of the most important goals is to prevent its micro- and macrovascular complications, and to that end, multifactorial intervention is widely recommended. Intensified multifactorial intervention with pharmacotherapy for associated risk factors, alongside lifestyle modification, was first shown to be efficacious in patients with microalbuminuria (Steno-2 study), then in those with less advanced microvascular complications (the Anglo-Danish-Dutch Study of Intensive Treatment In People with Screen Detected Diabetes in Primary Care [ADDITION]-Europe and the Japan Diabetes Optimal Treatment study for 3 major risk factors of cardiovascular diseases [J-DOIT3]), and in those with advanced microvascular complications (the Nephropathy In Diabetes-Type 2 [NID-2] study and Diabetic Nephropathy Remission and Regression Team Trial in Japan [DNETT-Japan]). Thus far, multifactorial intervention led to a reduction in cardiovascular and renal events, albeit not necessarily significant. It should be noted that not only baseline characteristics but also the control status of the risk factors and event rates during intervention among the patients widely varied from one trial to the next. Further evidence is needed for the efficacy of multifactorial intervention in a longer duration and in younger or elderly patients. Moreover, now that new classes of antidiabetic drugs are available, it should be addressed whether strict and safe glycemic control, alongside control of other risk factors, could lead to further risk reductions in micro- and macrovascular complications, thereby decreasing all-cause mortality in patients with type 2 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Idoso , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Fatores de Risco , Nefropatias Diabéticas/tratamento farmacológico , AlbuminúriaRESUMO
Diabetes is known to increase the risk of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Here we treat male STAM (STelic Animal Model) mice, which develop diabetes, NASH and HCC associated with dysbiosis upon low-dose streptozotocin and high-fat diet (HFD), with insulin or phlorizin. Although both treatments ameliorate hyperglycemia and NASH, insulin treatment alone lead to suppression of HCC accompanied by improvement of dysbiosis and restoration of antimicrobial peptide production. There are some similarities in changes of microflora from insulin-treated patients comorbid with diabetes and NASH. Insulin treatment, however, fails to suppress HCC in the male STAM mice lacking insulin receptor specifically in intestinal epithelial cells (ieIRKO), which show dysbiosis and impaired gut barrier function. Furthermore, male ieIRKO mice are prone to develop HCC merely on HFD. These data suggest that impaired gut insulin signaling increases the risk of HCC, which can be countered by restoration of insulin action in diabetes.
Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Experimental , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Masculino , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/patologia , Fígado/patologia , Carcinoma Hepatocelular/patologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Disbiose/complicações , Disbiose/patologia , Neoplasias Hepáticas/patologia , Insulina , Camundongos Endogâmicos C57BL , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de DoençasRESUMO
Leptin replacement therapy (LRT) has drastically improved the prognosis of patients with lipodystrophy, but pro-inflammatory properties of leptin could become evident in the long term. Here, we report a 30-year-old Japanese woman with generalized lipodystrophy-associated progeroid syndrome due to a heterozygous LMNA variant (c.29C > T; p.T10I), who was diagnosed with severe aortic stenosis (AS) after more than a decade of LRT, which required transcatheter aortic valve implantation. Given her marked hypoadiponectinemia and the LMNA variant, our patient might have been susceptible to progeria-associated disorders, including aortic stenosis, which could have been exaggerated by the prolonged 'imbalanced adipokines' caused by LRT between pro-inflammatory leptin and anti-inflammatory adiponectin. Thus, long-term LRT could be associated with AS in patients with the LMNA variant to cause generalized lipodystrophy-associated progeroid syndrome and hypoadiponectinemia.
Assuntos
Estenose da Valva Aórtica , Lipodistrofia Generalizada Congênita , Lipodistrofia , Adiponectina/deficiência , Adulto , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/cirurgia , Feminino , Humanos , Lamina Tipo A/genética , Leptina , Lipodistrofia/complicações , Lipodistrofia/diagnóstico , Lipodistrofia Generalizada Congênita/complicações , Erros Inatos do MetabolismoRESUMO
Myotonic dystrophy type 1 (DM1) displays a wide range of cardiac manifestations, including conduction system disturbances, arrhythmias, and cardiomyopathy. As a result of progressive myocardial injury and fibrosis, patients with DM1 frequently show electrocardiogram (ECG) abnormalities which sometimes cannot be differentiated from myocardial ischemia. Even in DM1 cases with ECG findings indicative of coronary artery disease, coronary angiography and coronary computed tomography often demonstrate intact coronary arteries. In this article, we report a case of a 56-year-old DM1 patient with ST segment change on ECG, who was admitted to our hospital for further examination. Echocardiography revealed severe hypokinesis in the anteroseptal wall and left ventricular thrombus in the apex, suggesting the possibility of an old myocardial infarction in the left anterior descending artery (LAD) region. Coronary computed tomography angiography and coronary angiography demonstrated a severe stenosis suggestive of vulnerable plaque in the proximal part of LAD, although fractional flow reserve of the lesion did not indicate functional ischemia. A beta-blocker and a sodium-glucose cotransporter 2 inhibitor were introduced expecting a cardioprotective effect. One year after his discharge, the patient died of septic and cardiogenic shock triggered by aspiration pneumonia. Learning objective: Although the prevalent cardiac manifestations of patients with myotonic dystrophy type 1 are conduction abnormalities and cardiomyopathy, the possibility of having coronary artery disease should be considered because they often have some atherosclerotic risk factors with their tendency toward metabolic abnormalities such as diabetes mellitus due to insulin resistance and dyslipidemia and with diagnostic difficulty due to asymptomatic or non-specific manifestations.
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Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. Here we show that mice with skeletal muscle-specific double knockout of Akt1/2, key downstream molecules of insulin signaling, serve as a model of premature sarcopenia with insulin resistance. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet. These phenotypes are almost reversed by additional knocking out of Foxo1/4, but only partially by additional knocking out of Tsc2 to activate the mTOR pathway. Overall, our data suggest that, unlike in lower organisms, suppression of Akt activity in skeletal muscle of mammals associated with insulin resistance and aging could accelerate osteosarcopenia and consequently reduce lifespan.