RESUMO
The discovery of insulin approximately a century ago greatly improved the management of diabetes, including many of its life-threatening acute complications like ketoacidosis. This breakthrough saved many lives and extended the healthy lifespan of many patients with diabetes. However, there is still a negative perception of ketone bodies stemming from ketoacidosis. Originally, ketone bodies were thought of as a vital source of energy during fasting and exercise. Furthermore, in recent years, research on calorie restriction and its potential impact on extending healthy lifespans, as well as studies on ketone bodies, have gradually led to a reevaluation of the significance of ketone bodies in promoting longevity. Thus, in this review, we discuss the emerging and hidden roles of ketone bodies in various organs, including the heart, kidneys, skeletal muscles, and brain, as well as their potential impact on malignancies and lifespan.
Assuntos
Diabetes Mellitus , Cetose , Humanos , Corpos Cetônicos , Longevidade , CoraçãoRESUMO
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations. Carriers of a mutation in the responsible genes are at risk of reaching end-stage kidney disease typically in middle age. The frequency of this disease is assumed to be underestimated because of a lack of disease-specific signs. Pathological findings obtained from kidney of uromodulin related ADTKD (ADTKD-UMOD) patients are regarded as non-specific and less-informative for its diagnosis. This research was undertaken to evaluate the significance of kidney biopsy in ADTKD-UMOD patients. METHODS: Thirteen patients from 10 families with nine identified uromodulin (UMOD) gene mutations who underwent kidney biopsy in the past were studied. Their kidney tissues were stained with anti-UMOD antibody in addition to conventional methods such as PAS staining. When positive, the numbers of tubules with visible UMOD protein accumulations were calculated based on the total numbers of UMOD expressing tubules. Pathological findings such as tubulointerstitial fibrosis, atrophy, inflammation and glomerulosclerosis were also evaluated and analyzed. RESULTS: Interstitial fibrosis and tubular atrophy were present in all 13 patients. Most atrophic tubules with thickening and lamellation of tubular basement membranes showed negative UMOD staining. In all but two patients with C94F mutations, massive accumulation of UMOD proteins was observed in the renal endoplasmic reticulum. UMOD accumulations were also detectable by PAS staining as polymorphic unstructured materials in the 11 patients at frequencies of 2.6-53.4%. 80.4% of the UMOD accumulations were surrounded by halos. The detection rate of UMOD accumulations positively correlated with eGFR. Glomerulosclerosis was detected in 11/13 patients, with a frequency of 20.0 to 61.1%, while no cystic dilatations of glomeruli were detected. CONCLUSIONS: Massively accumulated UMOD proteins in ADTKD-UMOD kidneys are detectable not only by immunostaining using anti-UMOD antibody but also by conventional methods such as PAS staining, although their detection is not easy. These findings can provide important clues to the diagnosis of ADTKD-UMOD. Kidney biopsy in ADTKD-UMOD may be more informative than assumed previously.
Assuntos
Rim/patologia , Rim Policístico Autossômico Dominante/patologia , Adolescente , Adulto , Biópsia , Feminino , Humanos , Túbulos Renais , Masculino , Pessoa de Meia-Idade , Mutação , Rim Policístico Autossômico Dominante/genética , Sensibilidade e Especificidade , Uromodulina/genética , Adulto JovemRESUMO
Dietary therapy is crucial for diabetes care with the aim of preventing the onset and progression of diabetes and its complications. The traditional approach to dietary therapy for diabetes has primarily focused on restricting the intake of the three major nutrients and rigorously controlling blood glucose levels. However, advancements in nutritional science have shown that within the three major nutrients - carbohydrates, proteins and lipids - there exist multiple types, each with distinct impacts on type 2 diabetes and its complications, sometimes even showing conflicting effects. In light of this, the present review shifts its focus from the quantity to the quality of the three major nutrients. It aims to provide an overview of how the differences in nutrient quality can influence onset and progression of type 2 diabetes and diabetic kidney disease, highlighting the diverse effects and, at times, contradictory impacts associated with each nutrient type.
Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Humanos , Nefropatias Diabéticas/dietoterapia , Nefropatias Diabéticas/prevenção & controle , Diabetes Mellitus Tipo 2/dietoterapia , Nutrientes/administração & dosagem , Valor Nutritivo , Carboidratos da Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagemRESUMO
For the advancement of DKD treatment, identifying unrecognized residual risk factors is essential. We explored the impact of obesity diversity derived from different carbohydrate qualities, with an emphasis on the increasing trend of excessive fructose consumption and its effect on DKD progression. In this study, we utilized db/db mice to establish a novel diabetic model characterized by fructose overconsumption, aiming to uncover the underlying mechanisms of renal damage. Compared to the control diet group, the fructose-fed db/db mice exhibited more pronounced obesity yet demonstrated milder glucose intolerance. Plasma cystatin C levels were elevated in the fructose model compared to the control, and this elevation was accompanied by enhanced glomerular sclerosis, even though albuminuria levels and tubular lesions were comparable. Single-cell RNA sequencing of the whole kidney highlighted an increase in Lrg1 in glomerular endothelial cells (GECs) in the fructose model, which appeared to drive mesangial fibrosis through enhanced TGF-ß1 signaling. Our findings suggest that excessive fructose intake exacerbates diabetic kidney disease progression, mediated by aberrant Lrg1-driven crosstalk between GECs and mesangial cells.
Assuntos
Nefropatias Diabéticas , Células Mesangiais , Camundongos , Animais , Células Endoteliais/patologia , Frutose/efeitos adversos , Nefropatias Diabéticas/patologia , Camundongos Endogâmicos , Obesidade/complicações , Comunicação CelularRESUMO
Accumulating evidence suggests health benefits of ketone bodies, and especially for longevity. However, the precise role of endogenous ketogenesis in mammalian life span, and the safety and efficacy of the long-term exogenous supplementation of ketone bodies remain unclear. In the present study, we show that a deficiency in endogenous ketogenesis, induced by whole-body Hmgcs2 deletion, shortens life span in mice, and that this is prevented by daily ketone body supplementation using a diet containing 1,3-butanediol, a precursor of ß-hydroxybutyrate. Furthermore, feeding the 1,3-butanediol-containing diet from early in life increases midlife mortality in normal mice, but in aged mice it extends life span and prevents the high mortality associated with atherosclerosis in ApoE-deficient mice. By contrast, an ad libitum low-carbohydrate ketogenic diet markedly increases mortality. In conclusion, endogenous ketogenesis affects mammalian survival, and ketone body supplementation may represent a double-edged sword with respect to survival, depending on the method of administration and health status.
Assuntos
Corpos Cetônicos , Longevidade , Camundongos , Animais , Butileno Glicóis , Ácido 3-Hidroxibutírico , MamíferosRESUMO
Potential-dependent dynamic adsorption-desorption and reorientation of a 4-pyridyl modified PAMAM G2 dendrimer at a Au(111) electrode has been demonstrated.