RESUMEN
In the past decade several novel findings point to the critical role of the skeleton in several homeostatic processes, including energy balance. The connection begins in the bone marrow with lineage allocation of mesenchymal stem cells to adipocytes or osteoblasts. Osteoblasts and adipocytes produce factors affecting insulin homeostasis. The hormonally active adipose tissue can regulate bone metabolism. In this review authors discuss targets taking critical part in the bone-fat network: leptin, osteocalcin, PPAR γ2 and the Wnt/beta catenin pathway. Leptin regulates energy metabolism through controlling appetite. Mutation of the leptin gene resulting leptin resistance leads to high leptin levels, enormous appetite and pathologic obesity. Leptin also can influence the bone mass. The main effects of the thiazolidinedions - PPARγ agonists - are mediated through receptors located in adipocytes. However, beside their positive effects, they also suppress osteoblastogenesis and increase the risk for pathologic fractures. Osteocalcin, a known marker of bone formation, produced by osteoblasts decreases fat mass, promotes adiponectin production and insulin sensitivity, increases the number of pancreatic ß-cells and increases insulin secretion. Thus, the skeletal system can regulate glucose metabolism and this substantially changed our view on this issue. Novel molecules can now be tested as targets in order to enhance bone formation and possibly prevent fractures.
Asunto(s)
Huesos/metabolismo , Diabetes Mellitus/metabolismo , Leptina/metabolismo , Peroxidación de Lípido , Osteocalcina/metabolismo , PPAR gamma/metabolismo , Proteína Wnt1/metabolismo , Animales , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Osteogénesis , Estrés Oxidativo , Transducción de SeñalRESUMEN
Angiotensin II (ANGII) plays a central role in the enhanced sodium reabsorption in early type 1 diabetes in man and in streptozotocin-induced (STZ) diabetic rats. This study investigates the effect of untreated STZ-diabetes leading to diabetic nephropathy in combination with ANGII treatment, on the abundance and localization of the renal Na(+),K(+)-ATPase (NKA), a major contributor of renal sodium handling. After 7 weeks of STZ-diabetes (i.v. 65 mg kg(-1)) a subgroup of control (C) and diabetic (D7) Wistar rats were treated with ANGII (s.c. minipump 33 microg kg(-1) h(-1) for 24 h; CA and D7A). We measured renal function and mRNA expression, protein level, Serin23 phosphorylation, subcellular distribution, and enzyme activity of NKA alpha-1 subunit in the kidney cortex. Diabetes increased serum creatinine and urea nitrogen levels (C versus D7), as did ANGII (C versus CA, D7 versus D7A). Both diabetes (C versus D7) and ANGII increased NKA alpha-1 protein level and enzyme activity (C versus CA, D7 versus D7A). Furthermore, the combination led to an additive increase (D7 versus D7A, CA versus D7A). NKA alpha-1 Ser23 phosphorylation was higher both in D7 and ANGII-treated rats in the non-cytoskeletal fraction, while no signal was detected in the cytoskeletal fraction. Control kidneys showed NKA alpha-1 immunopositivity on the basolateral membrane of proximal tubular cells, while both D7 and ANGII broadened NKA immunopositivity towards the cytoplasm. Our study demonstrates that diabetes mellitus (DM) increases the mRNA expression, protein level, Ser23 phosphorylation and enzyme activity of renal NKA, which is further elevated by ANGII. Despite an increase in total NKA quantity in diabetic nephropathy, the redistribution to the cystosol suggests the Na(+) pump is no longer functional. ANGII also caused translocation from the basolateral membrane, thus in diabetic states where ANGII level is acutely elevated, the loss of NKA will be exacerbated. This provides another mechanism by which ANGII blockade is likely to be protective.
Asunto(s)
Angiotensina II/farmacología , Diabetes Mellitus Experimental/metabolismo , Nefropatías Diabéticas/etiología , Riñón/efectos de los fármacos , Riñón/enzimología , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Animales , Sitios de Unión , Diabetes Mellitus Experimental/genética , Nefropatías Diabéticas/enzimología , Nefropatías Diabéticas/genética , Masculino , Fosforilación , Subunidades de Proteína , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , ATPasa Intercambiadora de Sodio-Potasio/química , ATPasa Intercambiadora de Sodio-Potasio/genéticaRESUMEN
Identification of ghrelin started with the discovery of growth hormone secretagogues, continued with the description of ghrelin receptors and ended with the elucidation of the chemical structure of ghrelin. However, several issues concerning the role of ghrelin in physiological and pathophysiological processes are still under investigation. Most of the ghrelin produced in the body is secreted in the stomach, but it is also expressed in the hypothalamus, pituitary, pancreas, intestine, kidney, heart and gonads. Ghrelin stimulates growth hormone secretion via growth hormone secretagogue receptors. Ghrelin secretion in the stomach depends on both acute and chronic changes in nutritional status and energy balance. Current data support the hypothesis that the stomach, in addition to its important role in digestion, not only influences pituitary hormone secretion but, via ghrelin production, it also sends orexigenic (appetite increasing) signals to hypothalamic nuclei involved in the regulation of energy homeostasis. In addition to these main effects, ghrelin influences insulin secretion and glucose metabolism and it may exert potentially important effects on cardiovascular and gastrointestinal functions. Because of its effects on a large number of physiological functions, ghrelin may be involved in the pathomechanism of several human disorders, including disturbances of appetite, energy homeostasis and glucose metabolism. Further research might lead to a better understanding of the pathophysiology of ghrelin and might provide more effective therapy for the above disorders.
Asunto(s)
Metabolismo Energético/fisiología , Ghrelina/fisiología , Glucosa/metabolismo , Hormona del Crecimiento/metabolismo , Animales , Fenómenos Fisiológicos Cardiovasculares/efectos de los fármacos , Diabetes Mellitus/fisiopatología , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/fisiología , Homeostasis/fisiología , Humanos , Insulina/metabolismo , Secreción de InsulinaRESUMEN
Type 1 diabetes is usually associated with other autoimmune diseases. Parietal cell antibodies (PCA) are found in 20% of type 1 diabetic patients which might be an early sign of autoimmune gastritis and pernicious anemia. PCA destroy the gastric H+/K+ ATP-ase. The chronic auto-destruction of the proton pump leads to hypo/achlorhydria and hypergastrinemia which leads to the hyper/dysplasia of enterochromaffin-like cells (ECL). ECL hyper/dysplasia is known to increase the likelihood of gastric carcinoid tumor development in affected patients. Gastric carcinoid tumors forming from the hyperplasia of ECL cells are found in 4-9% of patients having autoimmune gastritis or pernicious anemia. The 29-years-old type 1 diabetic patient, having primer hyperthyroidism was admitted to our clinic because of gastric pain. Results of endoscopy and biopsy showed multiple small polyps in the fundus with non-antral hypergastrinemic (type A) atrophic gastritis. The parietal cell antibody test was positive, the serum chromogranin A level was 289,7 ng/ml (normal value $ 98 ng/ml), TSH level was 9,93 mIU/L. The histological examination indicated carcinoid tumor. Sandostatin therapy was started then partial gastrectomy was done. After the operation the plasma chromogranin level normalized. Non-antral, multiple polyps could cover silent neuroendocrine tumors, which are slowly growing benign endocrine tumors, however, they also might be high malignity endocrine carcinomas. These tumors could be easily recognized in the clinical practice by measuring the serum or tissue chromogranin A level and other markers of tumor growth. Thus screening of gastric endocrine tumors in type 1 diabetic patients with co-morbid autoimmune diseases is recommended.
Asunto(s)
Biomarcadores de Tumor/sangre , Tumor Carcinoide/diagnóstico , Cromogranina A/sangre , Complicaciones de la Diabetes/diagnóstico , Diabetes Mellitus Tipo 1/complicaciones , Hipotiroidismo/complicaciones , Neoplasias Gástricas/diagnóstico , Adulto , Tumor Carcinoide/sangre , Tumor Carcinoide/etiología , Tumor Carcinoide/fisiopatología , Tumor Carcinoide/terapia , Complicaciones de la Diabetes/sangre , Complicaciones de la Diabetes/fisiopatología , Complicaciones de la Diabetes/terapia , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/fisiopatología , Femenino , Gastrectomía/métodos , Humanos , Hipotiroidismo/sangre , Hipotiroidismo/fisiopatología , Octreótido/uso terapéutico , Neoplasias Gástricas/sangre , Neoplasias Gástricas/etiología , Neoplasias Gástricas/fisiopatología , Neoplasias Gástricas/terapia , Tirotropina/sangreRESUMEN
BACKGROUND: Little is known about the pathophysiology of ghrelin secretion in growth hormone-deficient adults treated with growth hormone, and the relationship between plasma ghrelin and hyperinsulinemia induced by an oral glucose load has not been investigated in these patients. OBJECTIVE: In the present study we examined the relationship between plasma ghrelin, insulin, C-peptide and leptin after an oral glucose load in growth hormone-deficient adults receiving treatment with growth hormone. METHODS: Plasma ghrelin, leptin, insulin, C-peptide and blood glucose were measured before and then at 30, 60, 90 and 120 min after the ingestion of glucose (75 g orally) in 20 growth hormone-deficient adults (12 women and 8 men), who had been treated with growth hormone for 7.2 +/- 1.3 years (mean +/- SE). Plasma ghrelin was also determined before and after the glucose load in 10 age-and weight-matched healthy persons (5 women and 5 men). RESULTS: The oral glucose load induced a similar percent suppression of plasma ghrelin in the growth hormone-deficient patients and in the healthy persons. In both groups plasma ghrelin decreased significantly 30 min after the glucose load and remained suppressed throughout the test period. In the patients plasma insulin (baseline, 15.9 +/- 3.9 microIU/ml) and C-peptide (baseline, 2.5 +/- 0.3 ng/ml) showed opposite changes with peak responses at 30 min (insulin, 109.5 +/- 15.6 microIU/ml) or 60 min (C-peptide, 10.3 +/- 1.1 ng/ml). In these patients, post-glucose, but not baseline plasma ghrelin levels correlated negatively with plasma insulin, C-peptide and blood glucose levels, whereas baseline plasma ghrelin correlated inversely with baseline plasma leptin. CONCLUSIONS: The similar suppression of plasma ghrelin in growth hormone-deficient patients treated with growth hormone and in healthy persons after an oral glucose load argues against disturbed regulation of ghrelin secretion in these patients. The correlations between post-glucose plasma ghrelin, insulin and blood glucose support the existence of a previously proposed link between hyperinsulinemia (or increased blood glucose) and suppression of ghrelin levels.
Asunto(s)
Enanismo Hipofisario/sangre , Enanismo Hipofisario/tratamiento farmacológico , Glucosa/administración & dosificación , Hormona de Crecimiento Humana/administración & dosificación , Hormona de Crecimiento Humana/deficiencia , Hormonas Peptídicas/sangre , Administración Oral , Adulto , Femenino , Ghrelina , Humanos , Masculino , Tasa de Depuración Metabólica/efectos de los fármacosRESUMEN
Diabetes is known to increase the risk of Alzheimer's disease (AD) and vascular dementia via oxidative stress and inflammation. There are speculations that SSAO activity might be related to the development of AD. Our aim was to investigate whether changes of soluble SSAO activity, oxidative stress and inflammation markers are related to each other in diabetes. Soluble and tissue-bound SSAO activities (from serum and aorta, respectively) were determined in streptozotocin (STZ)-induced diabetic rats without insulin treatment, receiving insulin once, or twice daily compared to control animals. After three weeks of treatment soluble and tissue-bound SSAO activities (seSSAO and aoSSAO, respectively), serum total antioxidant status (TAS), high sensitivity C-reactive protein (hsCRP), fructose amine levels and routine laboratory parameters were determined. SeSSAO activity significantly increased in the diabetic groups without treatment and receiving insulin once daily, and a marked decrease in aoSSAO activity was seen in all diabetic groups. Increased oxidative stress was correlated with hsCRP elevation, while hsCRP and seSSAO activity were also significantly correlated. In all groups seSSAO and aoSSAO activities were in negative correlation with each other. Our results support the view that poor metabolic control leads to increased oxidative stress, which in turn may cause the elevation of hsCRP levels. Soluble SSAO on the one hand acts as an adhesion molecule--thus possibly being a factor responsible for the late complications of diabetes--and on the other hand, it may contribute to oxidative stress. Our parsimonious conclusion is that there is a relation between the risk factors of AD and vascular dementia (diabetes, oxidative stress and chronic inflammation) and SSAO activity, which may originate from the vessel wall.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/metabolismo , Encéfalo/metabolismo , Complicaciones de la Diabetes/metabolismo , Diabetes Mellitus Experimental/metabolismo , Encefalitis/metabolismo , Estrés Oxidativo/fisiología , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/fisiopatología , Animales , Antioxidantes/metabolismo , Encéfalo/fisiopatología , Proteína C-Reactiva/metabolismo , Arterias Cerebrales/metabolismo , Arterias Cerebrales/fisiopatología , Trastornos Cerebrovasculares/metabolismo , Trastornos Cerebrovasculares/fisiopatología , Enfermedad Crónica , Demencia Vascular/inducido químicamente , Demencia Vascular/metabolismo , Demencia Vascular/fisiopatología , Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus Experimental/fisiopatología , Modelos Animales de Enfermedad , Encefalitis/etiología , Encefalitis/fisiopatología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Activación Enzimática/fisiología , Fructosa/metabolismo , Masculino , Ratas , Ratas Wistar , Solubilidad , Regulación hacia Arriba/fisiologíaRESUMEN
Immunoglobulin A (IgA) nephropathy can rarely be associated with thyroid disease. We present a case of a young lady with nephrotic range proteinuria, microscopic hematuria, a creatinine clearance of 67 ml/min, biopsy proven IgA nephropathy, in whom hypercholesterolemia persisted after immunosuppressive therapy induced remission of glomerulonephritis. Fluvastatin was given but rhabdomyolysis developed. Unexpectedly, CK remained elevated following discontinuation of fluvastatin. Secondary amenorrhoea prompted endocrine work-up and hypothyroidism was diagnosed. Cholesterol, CK and TSH values became normal within 3 months on L-thyroxin therapy. The literature of the association of glomerular diseases and thyroid illness is reviewed. We would like to draw the attention to the possible association of glomerular pathologies and thyroid diseases and the importance of ruling out hypothyroidism and measuring CK level before starting statin therapy.
Asunto(s)
Glomerulonefritis por IGA/sangre , Hipercolesterolemia/complicaciones , Hipotiroidismo/complicaciones , Adulto , Biomarcadores/sangre , Biopsia , Colesterol/sangre , Creatinina/sangre , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glomerulonefritis por IGA/tratamiento farmacológico , Glomerulonefritis por IGA/patología , Humanos , Hipercolesterolemia/sangre , Hipercolesterolemia/tratamiento farmacológico , Hipotiroidismo/sangre , Hipotiroidismo/tratamiento farmacológico , Tirotropina/sangre , Tiroxina/uso terapéuticoRESUMEN
BACKGROUND: Hyperglycemia-induced oxidative stress and left ventricular hypertrophy is an independent risk factor for cardiovascular disease. Our aim was to determine the relationship between left ventricular hypertrophy and the total scavenger capacity (TSC) in diabetic rats. MATERIAL/METHODS: Control animals (n=30) were compared to streptozotocin-induced diabetic rats (n=38) and diabe-tic rats receiving insulin treatment (n=30) for 22 days. Half of the animals received angiotensin II on day 21. The left ventricular mass, TSC and carbohydrate parameters were determined. RESULTS: Diabetes did not alter left ventricular mass; however, diabetes with insulin treatment was associated with left ventricular hypertrophy. The extent of ventricular hypertrophy did not change significantly in this group after angiotensin II treatment. TSC increased very significantly in diabetic rats. These differences remained high when angiotensin II-treated control rats [CA] were compared with treated diabetic rats [DA] (p<0.005). TSC decreased significantly when diabetic rats were treated with insulin. CONCLUSIONS: Diabetes results in oxidative stress, which in turn enhances the activity of antioxidant enzymes. This increase in enzyme activity inhibits the subcellular remodeling processes, thus also inhibiting concomitant cardiac hypertrophy. Insulin treatment decreases the activity of the antioxidant system and can enhance the function of other localized tissue-specific growth factors. These changes may contribute to the early onset of cardiovascular damage detected in diabetic patients.
Asunto(s)
Antioxidantes/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Ventrículos Cardíacos/patología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Estrés Oxidativo , Angiotensina II/administración & dosificación , Angiotensina II/farmacología , Animales , Diabetes Mellitus Experimental/complicaciones , Ventrículos Cardíacos/efectos de los fármacos , Hipertrofia Ventricular Izquierda/etiología , Hipoglucemiantes/efectos adversos , Insulina/efectos adversos , Masculino , Ratas , Ratas WistarRESUMEN
OBJECTIVE: To gain insight into the cardiac adaptive mechanisms in diabetes, we studied whether angiotensin II (Ang II) alters expression of the atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and adrenomedullin (AM) genes in the left ventricle of the diabetic rat heart. METHODS: Diabetes was induced by streptozotocin (STZ; 60 mg/kg body weight intravenously). During the last 24 h of 2.5 or 7 weeks of treatment of male Wistar rats with STZ or vehicle, Ang II (33 microg/kg per h) was administered via osmotic minipumps. RESULTS: Diabetes was associated with an increased left ventricular weight to body weight (LV/BW) ratio, an index of left ventricular hypertrophy, at week 7 but not at week 2.5, and with increased ANP mRNA content at 2.5 weeks, but not with altered expression of the AM and BNP genes. Mean arterial pressure and LV/BW ratio were increased by Ang II in all groups except in the 7-week diabetic group. Levels of ANP mRNA were increased fourfold (P < 0.001) and threefold (P < 0.05) by Ang II at 2.5 and 7 weeks in control animals, respectively, and 11-fold (P < 0.001) and sevenfold (P < 0.001) at 2.5 and 7 weeks in diabetic animals, respectively. Ang II increased ventricular concentrations of BNP mRNA in control and diabetic animals at 2.5 weeks (1.3-fold, P < 0.001; and 1.6-fold, P < 0.001) and at 7 weeks (1.3-fold, P < 0.05; and 1.8-fold, P < 0.001), respectively. Left ventricular levels of adrenomedullin mRNA were increased by treatment with Ang II for 24 h in 2.5-week diabetic animals. CONCLUSION: Ang II markedly increased the levels of natriuretic peptide mRNAs in the left ventricle of normal and diabetic rat hearts, whereas it increased adrenomedullin mRNA levels only in 2.5-week diabetic rats and failed to cause hypertension in 7-week diabetic rats. Left ventricular levels of ANP and BNP mRNA were increased by Ang II in diabetic animals more than the additive effects of diabetes and Ang II alone, showing that Ang II induced an amplified response with respect to cardiac concentrations of ANP and BNP in diabetes.
Asunto(s)
Angiotensina II/metabolismo , Factor Natriurético Atrial/metabolismo , Diabetes Mellitus Experimental/metabolismo , Ventrículos Cardíacos/metabolismo , Hipertrofia Ventricular Izquierda/metabolismo , Péptido Natriurético Encefálico/metabolismo , Péptidos/metabolismo , Adrenomedulina , Angiotensina II/genética , Animales , Antihipertensivos/metabolismo , Factor Natriurético Atrial/genética , Masculino , Péptido Natriurético Encefálico/genética , Péptidos/genética , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factores de Tiempo , Regulación hacia ArribaRESUMEN
INTRODUCTION: In diabetes the heart rate variability is decreased because of the autonomic neuropathy and parallel with this phenomenon the overnight blood pressure fall is lost. Presumably this change in the hemodynamic parameters is connected with the fact that the cardiovascular complications in type 1 diabetic patients are 2-4 times more frequent than in healthy patients. The volatility, as a new factor, is the dispersion of the proportion of the blood pressure values following each other. It exactly reflects the 24-hour blood pressure fluctuation, while the dipper/non-dipper determination differentiates only between the daytime and night-time average blood pressure values. The volatility follows the changes of the measured values in accordance to the frequency of the measurements during the whole day. AIM: Our aim was to compare the blood pressure variability of type 1 diabetic patients (DM) and healthy controls (C). PATIENTS AND METHODS: The authors examined 43 diabetic patients from our outpatient clinic and 45 healthy people. The blood pressures were measured with Meditech ABPM 02 monitor on workdays. The measurements started in the mornings. The frequency of the measurements was 20 minutes during the day and 50 minutes at night-time. The authors took the history of all the patients and detailed laboratory results. The patients also had ophthalmology examination, ECG and echocardiography tests. RESULTS: During the Ambulatory Blood Pressure Monitoring we found that the systolic volatility of blood pressure values was significantly lower in DM compared to C patients. Systolic volatility: 0.133 +/- 0.011 vs. 0.175 +/- 0.014 p < 0.026. Comparing only the normotonic C and DM group systolic volatility of blood pressure values were significantly lower in DM. Systolic volatility: 0.128 +/- 0.016 vs. 0.177 +/- 0.021 p < 0.036. CONCLUSION: It is an important new finding that in type 1 diabetic patient the volatility--a new parameter for determining blood pressure variability--is lower than in the healthy control group. At normotension state other parameters describing the blood pressure variability (like diurnal index or standard deviation) could not show this change.