RESUMEN
AIMS/HYPOTHESIS: Melanocortin 4 receptor (MC4R) mutation is the most common cause of known monogenic obesity in humans. Unexpectedly, humans and rodents with MC4R deficiency do not develop hyperglycaemia despite chronic obesity and insulin resistance. To explain the underlying mechanisms for this phenotype, we determined the role of MC4R in glucose homeostasis in the presence and absence of obesity in mice. METHODS: We used global and hypothalamus-specific MC4R-deficient mice to investigate the brain regions that contribute to glucose homeostasis via MC4R. We performed oral, intraperitoneal and intravenous glucose tolerance tests in MC4R-deficient mice that were either obese or weight-matched to their littermate controls to define the role of MC4R in glucose regulation independently of changes in body weight. To identify the integrative pathways through which MC4R regulates glucose homeostasis, we measured renal and adrenal sympathetic nerve activity. We also evaluated glucose homeostasis in adrenaline (epinephrine)-deficient mice to investigate the role of adrenaline in mediating the effects of MC4R in glucose homeostasis. We employed a graded [13C6]glucose infusion procedure to quantify renal glucose reabsorption in MC4R-deficient mice. Finally, we measured the levels of renal glucose transporters in hypothalamus-specific MC4R-deficient mice and adrenaline-deficient mice using western blotting to ascertain the molecular mechanisms underlying MC4R control of glucose homeostasis. RESULTS: We found that obese and weight-matched MC4R-deficient mice exhibited improved glucose tolerance due to elevated glucosuria, not enhanced beta cell function. Moreover, MC4R deficiency selectively in the paraventricular nucleus of the hypothalamus (PVH) is responsible for reducing the renal threshold for glucose as measured by graded [13C6]glucose infusion technique. The MC4R deficiency suppressed renal sympathetic nerve activity by 50% in addition to decreasing circulating adrenaline and renal GLUT2 levels in mice, which contributed to the elevated glucosuria. We further report that adrenaline-deficient mice recapitulated the increased excretion of glucose in urine observed in the MC4R-deficient mice. Restoration of circulating adrenaline in both the MC4R- and adrenaline-deficient mice reversed their phenotype of improved glucose tolerance and elevated glucosuria, demonstrating the role of adrenaline in mediating the effects of MC4R on glucose reabsorption. CONCLUSIONS/INTERPRETATION: These findings define a previously unrecognised function of hypothalamic MC4R in glucose reabsorption mediated by adrenaline and renal GLUT2. Taken together, our findings indicate that elevated glucosuria due to low sympathetic tone explains why MC4R deficiency does not cause hyperglycaemia despite inducing obesity and insulin resistance. Graphical abstract.
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Hexosas/metabolismo , Homeostasis/fisiología , Receptor de Melanocortina Tipo 4/fisiología , Bases de Schiff/metabolismo , Animales , Glucemia/metabolismo , Cruzamientos Genéticos , Epinefrina/deficiencia , Epinefrina/fisiología , Prueba de Tolerancia a la Glucosa , Transportador de Glucosa de Tipo 2/fisiología , Glucosuria/fisiopatología , Hipotálamo/química , Insulina/sangre , Resistencia a la Insulina/fisiología , Riñón/inervación , Riñón/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/fisiopatología , Receptor de Melanocortina Tipo 4/deficiencia , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
OBJECTIVE: Hypothalamic arcuate nucleus-specific pro-opiomelanocortin deficient (ArcPomc-/-) mice exhibit improved glucose tolerance despite massive obesity and insulin resistance. We demonstrated previously that their improved glucose tolerance is due to elevated glycosuria. However, the underlying mechanisms that link glucose reabsorption in the kidney with ArcPomc remain unclear. Given the function of the hypothalamic melanocortin system in controlling sympathetic outflow, we hypothesized that reduced renal sympathetic nerve activity (RSNA) in ArcPomc-/- mice could explain their elevated glycosuria and consequent enhanced glucose tolerance. METHODS: We measured RSNA by multifiber recording directly from the nerves innervating the kidneys in ArcPomc-/- mice. To further validate the function of RSNA in glucose reabsorption, we denervated the kidneys of WT and diabetic db/db mice before measuring their glucose tolerance and urine glucose levels. Moreover, we performed western blot and immunohistochemistry to determine kidney GLUT2 and SGLT2 levels in either ArcPomc-/- mice or the renal-denervated mice. RESULTS: Consistent with our hypothesis, we found that basal RSNA was decreased in ArcPomc-/- mice relative to their wild type (WT) littermates. Remarkably, both WT and db/db mice exhibited elevated glycosuria and improved glucose tolerance after renal denervation. The elevated glycosuria in obese ArcPomc-/-, WT and db/db mice was due to reduced renal GLUT2 levels in the proximal tubules. Overall, we show that renal-denervated WT and diabetic mice recapitulate the phenotype of improved glucose tolerance and elevated glycosuria associated with reduced renal GLUT2 levels observed in obese ArcPomc-/- mice. CONCLUSION: Hence, we conclude that ArcPomc is essential in maintaining basal RSNA and that elevated glycosuria is a possible mechanism to explain improved glucose tolerance after renal denervation in drug resistant hypertensive patients.
Asunto(s)
Glucosuria/fisiopatología , Hipotálamo/metabolismo , Riñón/inervación , Proopiomelanocortina/deficiencia , Sistema Nervioso Simpático/fisiología , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Diabetes Mellitus Experimental , Femenino , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Transportador de Glucosa de Tipo 2/metabolismo , Glucosuria/metabolismo , Glucosuria/orina , Insulina/metabolismo , Resistencia a la Insulina/fisiología , Riñón/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Obesos , Obesidad/metabolismo , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismoRESUMEN
BACKGROUND: In experimental settings, uranium is toxic to kidneys, but effects on humans are unclear. Ingestion of water from drilled wells is a source of high uranium exposure in some populations. METHODS: Uranium exposure was measured in 95 men and 98 women aged 18 to 81 years who had used drinking water from drilled wells for an average of 16 years. Urinary N-acetyl-gamma-d-glucosaminidase, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyltransferase, and glutathione-S-transferase; serum cystatin C; and urinary and serum calcium, phosphate, glucose, and creatinine were measured to evaluate possible toxic effects of uranium on kidney cells and renal function. In addition, supine blood pressure was measured. Associations between uranium exposure and the outcome variables were modeled by using linear regression with adjustment for age, sex, body mass index, smoking, and analgesic use. RESULTS: Median uranium concentration in drinking water was 25 microg/L (interquartile range, 5 to 148 microg/L; maximum, 1,500 microg/L). Indicators of cytotoxicity and kidney function did not show evidence of renal damage. No statistically significant associations with uranium in urine, water, hair, or toenails was found for 10 kidney toxicity indicators. Uranium exposure was associated with greater diastolic and systolic blood pressures, and cumulative uranium intake was associated with increased glucose excretion in urine. CONCLUSION: Continuous uranium intake from drinking water, even at relatively high exposures, was not found to have cytotoxic effects on kidneys in humans.
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Ingestión de Líquidos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/orina , Uranio/administración & dosificación , Uranio/toxicidad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Fosfatasa Alcalina/orina , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Calcio/orina , Contaminantes Ambientales/administración & dosificación , Contaminantes Ambientales/toxicidad , Femenino , Finlandia , Glutatión Transferasa/orina , Glucosuria/inducido químicamente , Glucosuria/diagnóstico , Glucosuria/fisiopatología , Glucosuria/orina , Hexosaminidasas/orina , Humanos , Hipertensión/inducido químicamente , Hipertensión/diagnóstico , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Riñón/patología , Riñón/fisiopatología , Enfermedades Renales/diagnóstico , Enfermedades Renales/fisiopatología , Pruebas de Función Renal , L-Lactato Deshidrogenasa/orina , Masculino , Persona de Mediana Edad , Análisis Multivariante , Uranio/farmacología , Uranio/orina , gamma-Glutamiltransferasa/orinaRESUMEN
During initial trials of 5-azacytidine in adults with advanced acute leukemia, we unexpectedly observed acid-base, fluid, and electrolyte abnormalities that contributed directly to the deaths of two early patients. To evaluate this toxicity further, we studied 22 patients who received a total of 33 courses of combination chemotherapy that included 5-azacytidine. During 29 courses (88%) of treatment, polyuria, glucosuria, and/or transient changes in the serum concentrations of bicarbonate or phosphorus were detected. Spontaneous polyuria with demonstrable salt wasting and orthostatic hypotension occurred during seven courses (21%) of treatment. Inappropriate glucosuria was observed in nine courses (27%). In 24 courses (73%) the serum bicarbonate fell below the normal range. The urine became alkaline during 12 of these instances; the anion gap was not increased during the acidosis. Hypophosphatemia with serum phosphorus concentrations as low as 0.3 mg/dl occurred in 21 of 32 evaluable courses (66%). In the three patients studied the tubular reabsorption of phosphorus was 10%-18%. The renal abnormalities that were observed suggest both proximal and distal tubular damage from 5-azacytidine. Patients receiving 5-azacytidine should be monitored closely for manifestations of renal toxicity.