RESUMEN
PURPOSE: Human trophoblast cell surface antigen 2 (Trop-2) is a protein highly expressed in urothelial cancer (UC). Sacituzumab govitecan (SG) is a Trop-2-directed antibody drug conjugate with a hydrolysable linker and a potent SN-38 payload. This study explored Trop-2 expression in tumors treated with SG in cohorts 1 to 3 (C1-3) from the TROPHY-U-01 study and evaluated whether efficacy was associated with Trop-2 expression. PATIENTS AND METHODS: TROPHY-U-01 (NCT03547973) is an open-label phase II study that assessed the efficacy and safety of SG (alone or in combinations) in patients with unresectable locally advanced or metastatic UC (mUC). Archival tumor samples collected at enrollment for C1-3 were analyzed for Trop-2 membrane expression by considering histological scores (H-scores; scale 0-300) and the percentage of membrane positive tumor cells at low magnification (4×). The association of Trop-2 with clinical endpoints [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] was evaluated. RESULTS: In C1-3, tissue was collected from 158 (82%) of 192 treated patients, and 146 (76%) had evaluable Trop-2 data. Trop-2 was highly expressed in tumor samples. The median [interquartile range (IQR)] Trop-2 H-score was 215 (180-246), and the median (IQR) percentage of membrane positive tumor cells was 91% (80-98). Trop-2 expression at any level was observed in 98% of patients. Furthermore, ORR, PFS, and OS benefits were observed across all Trop-2 expression levels. CONCLUSIONS: Trop-2 protein is highly expressed in UC, as confirmed by examining tumors from patients enrolled in the TROPHY-U-01 trial. The results indicate that SG demonstrates efficacy in mUC across Trop-2 expression levels.
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Anticuerpos Monoclonales Humanizados , Antígenos de Neoplasias , Camptotecina , Moléculas de Adhesión Celular , Inmunoconjugados , Humanos , Moléculas de Adhesión Celular/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Masculino , Anciano , Persona de Mediana Edad , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Inmunoconjugados/uso terapéutico , Anciano de 80 o más Años , Adulto , Biomarcadores de Tumor/metabolismo , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias Urológicas/mortalidad , Neoplasias Urológicas/metabolismo , Resultado del Tratamiento , Estadificación de NeoplasiasRESUMEN
WHAT IS THIS SUMMARY ABOUT?: Sacituzumab govitecan (brand name: TRODELVY®) is a new treatment being studied for people with a type of bladder cancer, called urothelial cancer, that has progressed to a locally advanced or metastatic stage. Locally advanced and metastatic urothelial cancer are usually treated with platinum-based chemotherapy. Metastatic urothelial cancer is also treated with immune checkpoint inhibitors. There are few treatment options for people whose cancer gets worse after receiving these treatments. Sacituzumab govitecan is a suitable treatment option for most people with urothelial cancer because it aims to deliver an anti-cancer drug directly to the cancer in an attempt to limit the potential harmful side effects on healthy cells. This is a summary of a clinical study called TROPHY-U-01, focusing on the first group of participants, referred to as Cohort 1. All participants in Cohort 1 received sacituzumab govitecan. WHAT ARE THE KEY TAKEAWAYS?: All participants received previous treatments for their metastatic urothelial cancer, including a platinum-based chemotherapy and a checkpoint inhibitor. The tumor in 31 of 113 participants became significantly smaller or could not be seen on scans after sacituzumab govitecan treatment; an effect that lasted for a median of 7.2 months. Half of the participants were still alive 5.4 months after starting treatment, without their tumor getting bigger or spreading further. Half of them were still alive 10.9 months after starting treatment regardless of tumor size changes. Most participants experienced side effects. These side effects included lower levels of certain types of blood cells, sometimes with a fever, and loose or watery stools (diarrhea). Side effects led 7 of 113 participants to stop taking sacituzumab govitecan. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The study showed that sacituzumab govitecan had significant anti-cancer activity. Though most participants who received sacituzumab govitecan experienced side effects, these did not usually stop participants from continuing sacituzumab govitecan. Doctors can help control these side effects using treatment guidelines, but these side effects can be serious.Clinical Trial Registration: NCT03547973 (ClinicalTrials.gov) (TROPHY-U-1).
RESUMEN
PURPOSE: Pembrolizumab is standard therapy for patients with metastatic urothelial cancer (mUC) who progress after first-line platinum-based chemotherapy; however, only approximately 21% of patients respond. Sacituzumab govitecan (SG) is a trophoblast cell surface antigen-2-directed antibody-drug conjugate with US Food and Drug Administration-accelerated approval to treat patients with locally advanced or mUC who previously received platinum-based chemotherapy and a checkpoint inhibitor (CPI). Here, we report the primary analysis of TROPHY-U-01 cohort 3. METHODS: TROPHY-U-01 (ClinicalTrials.gov identifier: NCT03547973) is a multicohort, open-label phase II study. Patients were CPI-naïve and had mUC progression after platinum-based chemotherapy in the metastatic setting or ≤12 months in the (neo)adjuvant setting. Patients received 10 mg/kg of SG once on days 1 and 8 and 200 mg of pembrolizumab once on day 1 of 21-day cycles. The primary end point was objective response rate (ORR) per central review. Secondary end points included clinical benefit rate (CBR), duration of response (DOR) and progression-free survival (PFS) per central review, and safety. RESULTS: Cohort 3 included 41 patients (median age 67 years; 83% male; 78% visceral metastases [29% liver]). With a median follow-up of 14.8 months, the ORR was 41% (95% CI, 26.3 to 57.9; 20% complete response rate), CBR was 46% (95% CI, 30.7 to 62.6), median DOR was 11.1 months (95% CI, 4.8 to not estimable [NE]), and median PFS was 5.3 months (95% CI, 3.4 to 10.2). The median overall survival was 12.7 months (range, 10.7-NE). Grade ≥3 treatment-related adverse events occurred in 61% of patients; most common were neutropenia (37%), leukopenia (20%), and diarrhea (20%). CONCLUSION: SG plus pembrolizumab demonstrated a high response rate with an overall manageable toxicity profile in patients with mUC who progressed after platinum-based chemotherapy. No new safety signals were detected. These data support further evaluation of SG plus CPI in mUC.
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Anticuerpos Monoclonales Humanizados , Camptotecina/análogos & derivados , Carcinoma de Células Transicionales , Inmunoconjugados , Humanos , Masculino , Anciano , Femenino , Platino (Metal)/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Inmunoconjugados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: Human aging is associated with heightened risk of diabetes and cardiovascular disease. Increased fat mass may contribute to age-related diseases by harboring inflammatory macrophages that produce metabolically important proteins such as plasminogen activator inhibitor-1 (PAI-1). Elevated PAI-1 concentrations have been implicated in the pathogenesis of such aging-related conditions as insulin resistance, obesity, and atherosclerosis. We have previously reported that increased plasma free fatty acid (FFA) concentrations augment both circulating PAI-1 concentrations and PAI-1 production by adipose tissue macrophages (ATMs). METHODS: Because increasing age is associated with increased infiltration and reactivity of adipose macrophages, we performed euglycemic-hyperinsulinemic clamp studies and adipose tissue biopsies with and without elevated FFA concentrations in 31 nondiabetic participants stratified by age, to determine whether middle-aged individuals manifest heightened insulin resistance and PAI-1 production by ATMs in response to elevated nutrient signals relative to their young adult peers. RESULTS: We observed that elevating FFA concentrations under euglycemic-hyperinsulinemic clamp conditions induced the same degree of insulin resistance in both middle-aged and younger body mass index-matched adults, whereas systemic PAI-1 concentrations were significantly increased in the middle-aged group. Likewise, elevated FFA and insulin concentrations induced larger increases in PAI-1 gene expression in the whole fat and ATMs of middle-aged compared with younger adult participants. CONCLUSIONS: These studies reveal a heightened adipose inflammatory response to increased FFA and insulin availability in middle-aged individuals relative to younger adults, suggesting that increased susceptibility to the effects of fatty acid excess may contribute to the pathogenesis of age-related diseases.
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Tejido Adiposo/metabolismo , Envejecimiento/fisiología , Ácidos Grasos no Esterificados/fisiología , Macrófagos/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Adulto , Anciano , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Resistencia a la Insulina/fisiología , Activación de Macrófagos/fisiología , Masculino , Persona de Mediana Edad , Reacción en Cadena en Tiempo Real de la Polimerasa , Adulto JovenRESUMEN
Macrophages are more abundant in adipose tissue from obese individuals than from those of normal weight and may contribute to the metabolic consequences of obesity by producing various circulating factors. One of these factors is plasminogen activator inhibitor-1 (PAI-1), which contributes to both atherosclerosis and insulin resistance. Because nutritional factors appear to regulate PAI-1 expression, we hypothesized that exposure to fatty acids and adipocyte secretory products could stimulate production of PAI-1 by adipose macrophages. Increased free fatty acid (FFA) concentrations in blood for 5 hours in nondiabetic, overweight subjects markedly suppressed insulin-stimulated glucose uptake and raised circulating PAI-1 concentrations, with a concomitant increase in the expression of the PAI-1 gene in adipose tissue. FFAs also rapidly increased PAI-1 gene expression in adipose macrophages and PAI-1 protein immunofluorescence surrounding these cells. By contrast, PAI-1 expression in circulating monocytes was very low and was not affected by raising the concentration of FFAs. Medium from cultured adipocytes stimulated PAI-1 expression in cultured macrophages and potentiated the increase in PAI-1 messenger RNA expression in response to FFAs. Together, our data suggest that adipocyte-derived factors prime adipose macrophages so that they respond to nutritional signals (FFAs) by releasing a key inflammatory adipokine, PAI-1.
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Adipocitos/metabolismo , Ácidos Grasos no Esterificados/sangre , Macrófagos/inmunología , Obesidad/fisiopatología , Inhibidor 1 de Activador Plasminogénico/metabolismo , Adipocitos/citología , Adipoquinas/sangre , Adipoquinas/inmunología , Animales , Glucemia/metabolismo , Péptido C/sangre , Diabetes Mellitus Tipo 2/inmunología , Diabetes Mellitus Tipo 2/fisiopatología , Femenino , Técnica de Clampeo de la Glucosa , Humanos , Insulina/sangre , Macrófagos/citología , Masculino , Ratones , Obesidad/inmunologíaRESUMEN
Glucose effectiveness, the ability of glucose per se to suppress endogenous glucose production (EGP), is lost in type 2 diabetes mellitus (T2DM). Free fatty acids (FFA) may contribute to this loss of glucose effectiveness in T2DM by increasing gluconeogenesis (GNG) and impairing the response to hyperglycemia. Thus, we first examined the effects of increasing plasma FFA levels for 3, 6, or 16 h on glucose effectiveness in nondiabetic subjects. Under fixed hormonal conditions, hyperglycemia suppressed EGP by 61% in nondiabetic subjects. Raising FFA levels with Liposyn infusion for > or =3 h reduced the normal suppressive effect of glucose by one-half. Second, we hypothesized that inhibiting GNG would prevent the negative impact of FFA on glucose effectiveness. Raising plasma FFA levels increased gluconeogenesis by approximately 52% during euglycemia and blunted the suppression of EGP by hyperglycemia. Infusion of ethanol rapidly inhibited GNG and doubled the suppression of EGP by hyperglycemia, thereby restoring glucose effectiveness. In conclusion, elevated FFA levels rapidly increased GNG and impaired hepatic glucose effectiveness in nondiabetic subjects. Inhibiting GNG could have therapeutic potential in restoring the regulation of glucose production in type 2 diabetes mellitus.
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Etanol/farmacología , Ácidos Grasos no Esterificados/farmacología , Gluconeogénesis/efectos de los fármacos , Glucosa/metabolismo , Adulto , Regulación hacia Abajo/efectos de los fármacos , Eficiencia/efectos de los fármacos , Femenino , Técnica de Clampeo de la Glucosa/métodos , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
Recent studies have indicated that the mass/content of intramyocellular lipid (IMCL), intrahepatic triglyceride (IHTG), visceral fat (VF), and even deep abdominal subcutaneous fat (SF) may all be correlated with insulin resistance. Since simultaneous measurements of these parameters have not been reported, the relative strength of their associations with insulin action is not known. Therefore, the goals of this study were 1) to simultaneously measure IMCL, IHTG, VF, and abdominal SF in the same nondiabetic individuals using noninvasive (1)H-magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) and 2) to examine how these fat stores are correlated with systemic insulin sensitivity as measured by whole body glucose disposal (R(d)) during euglycemic-hyperinsulinemic clamp studies. Positive correlations were observed among IMCL, IHTG, and VF. There were significant inverse correlations between whole body R(d) and both IMCL and VF. Notably, there was a particularly tight inverse correlation between IHTG and whole body R(d) (r = -0.86, P < 0.001), consistent with an association between liver fat and peripheral insulin sensitivity. This novel finding suggests that hepatic triglyceride accumulation has important systemic consequences that may adversely affect insulin sensitivity in other tissues.
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Resistencia a la Insulina/fisiología , Hígado/química , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Triglicéridos/análisis , Adiponectina/sangre , Adulto , Quimiocina CCL2/sangre , Técnica de Clampeo de la Glucosa , Humanos , Interleucina-6/sangre , Grasa Intraabdominal/metabolismo , Leptina/sangre , Metabolismo de los Lípidos , Lípidos/análisis , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Resistina/sangre , Grasa Subcutánea Abdominal/metabolismo , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Circulating adiponectin levels are increased by the thiazolidinedione (TZD) class of PPARgamma agonists in concert with their insulin-sensitizing effects. Two receptors for adiponectin (AdipoR1 and AdipoR2) are widely expressed in many tissues, but their physiological significance to human insulin resistance remains to be fully elucidated. We examined the expression patterns of AdipoR1 and AdipoR2 in fat and skeletal muscle of human subjects, their relationship to insulin action, and whether they are regulated by TZDs. Expression patterns of both AdipoRs were similar in subcutaneous and omental fat depots, with higher expression in adipocytes than in stromal cells and macrophages. To determine the effects of TZDs on AdipoR expression, subcutaneous fat and quadriceps muscle were biopsied in 14 insulin-resistant subjects with type 2 diabetes mellitus after 45 mg pioglitazone or placebo for 21 days. This duration of pioglitazone improved insulin's suppression of glucose production by 41% and enhanced stimulation of glucose uptake by 27% in concert with increased gene expression and plasma levels of adiponectin. Pioglitazone did not affect AdipoR expression in muscle, whole fat, or cellular adipose fractions, and receptor expression did not correlate with baseline or TZD-enhanced insulin action. In summary, both adiponectin receptors are expressed in cellular fractions of human fat, particularly adipocytes. TZD administration for sufficient duration to improve insulin action and increase adiponectin levels did not affect expression of AdipoR1 or AdipoR2. Although TZDs probably exert many of their effects via adiponectin, changes in these receptors do not appear to be necessary for their insulin-sensitizing effects.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Insulina/farmacología , Receptores de Superficie Celular/biosíntesis , Tiazolidinedionas/farmacología , Adiponectina/biosíntesis , Adiponectina/genética , Adulto , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Método Doble Ciego , Sinergismo Farmacológico , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Técnica de Clampeo de la Glucosa , Humanos , Insulina/metabolismo , Grasa Intraabdominal/efectos de los fármacos , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/fisiología , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiología , Pioglitazona , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores de Adiponectina , Receptores de Superficie Celular/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Grasa Subcutánea/efectos de los fármacos , Grasa Subcutánea/metabolismo , Grasa Subcutánea/fisiologíaRESUMEN
Impaired effectiveness of glucose to suppress endogenous glucose production (EGP) is an important cause of worsening hyperglycemia in type 2 diabetes. Elevated free fatty acids (FFAs) may impair glucose effectiveness via several mechanisms, including rapid changes in metabolic fluxes and/or more gradual changes in gene expression of key enzymes or other proteins. Thus, we examined the magnitude and time course of effects of FFAs on glucose effectiveness in type 2 diabetes and whether glucose effectiveness can be restored by lowering FFAs. Glucose fluxes ([3-(3)H]-glucose) were measured during 6-h pancreatic clamp studies, at euglycemia (5 mmol/l glucose, t=0-240 min), and hyperglycemia (10 mmol/l, t=240-360 min). We studied 19 poorly controlled subjects with type 2 diabetes (HbA(1c) 10.9 +/- 0.4%, age 50 +/- 3 years, BMI 30 +/- 2 kg/m(2)) on at least two occasions with saline (NA- group) or nicotinic acid (NA group) infusions for 3, 6, or 16 h (NA3h, NA6h, and NA16h groups, respectively) to lower FFAs to nondiabetic levels. As a reference group, glucose effectiveness was also assessed in 15 nondiabetic subjects. There was rapid improvement in hepatic glucose effectiveness following only 3 h of NA infusion (NA3h = 31 +/- 6% suppression of EGP with hyperglycemia vs. NA- = 8 +/- 7%; P<0.01) and complete restoration of glucose effectiveness after 6 h of NA (NA6h = 41 +/- 8% suppression of EGP; P = NS vs. nondiabetic subjects). Importantly, the loss of hepatic glucose effectiveness in type 2 diabetes is completely reversible upon correcting the increased FFA concentrations. A longer duration of FFA lowering may be required to overcome the chronic effects of increased FFAs on hepatic glucose effectiveness.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 2/patología , Diabetes Mellitus Tipo 2/fisiopatología , Ácidos Grasos no Esterificados/fisiología , Técnica de Clampeo de la Glucosa , Glicerol/metabolismo , Humanos , Hiperglucemia/metabolismo , Hiperglucemia/patología , Hiperglucemia/prevención & control , Persona de Mediana Edad , Niacina/administración & dosificación , Niacina/farmacología , Cloruro de Sodio/administración & dosificación , Cloruro de Sodio/farmacología , Factores de TiempoRESUMEN
PURPOSE OF REVIEW: 'Glucose effectiveness' refers to the ability of glucose per se to suppress endogenous glucose production and stimulate glucose uptake. In addition to the inhibitory effects of insulin on endogenous glucose production, rising glucose levels have important direct effects on glucose homeostasis. The loss of glucose effectiveness in type 2 diabetes mellitus contributes importantly to hyperglycemia in those individuals. Given the rapidly increasing incidence and serious complications of type 2 diabetes mellitus, understanding the regulation of glucose effectiveness has great potential therapeutic benefits. RECENT FINDINGS: The loss of this important regulation appears to be secondary to the chronic 'diabetic milieu' in type 2 diabetes mellitus, which includes elevated plasma glucose and free fatty acid levels. Glucose effectiveness is completely restored by normalizing plasma free fatty acid levels. Increased free fatty acid availability stimulates gluconeogenesis and alters flux through key hepatic enzymes. It is likely that at least part of this regulation is through central pathways. In addition, hormones that may exert important effects on hepatic glucose effectiveness include cortisol, insulin and glucagon-like peptide 1. The effectiveness of glucose to stimulate glucose uptake is impaired by elevated free fatty acid levels and may be enhanced by glucagon-like peptide 1. SUMMARY: The regulation of glucose effectiveness involves a complex interplay of hormonal and metabolic factors, with free fatty acid and glucoregulatory hormones playing key roles. The loss of this regulation in type 2 diabetes mellitus contributes importantly to hyperglycemia, and may largely be caused by increased free fatty acid levels.
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Glucosa/fisiología , Homeostasis/fisiología , Hiperglucemia/metabolismo , Insulina/metabolismo , Glucemia/metabolismo , Ácidos Grasos Volátiles/sangre , Ácidos Grasos Volátiles/fisiología , Glucosa/biosíntesis , Glucosa/metabolismo , HumanosRESUMEN
Whereas thiazolidinediones (TZDs) are known to rapidly improve insulin action in animals, short durations of TZD therapy have never been studied in humans. Among the many known actions of TZDs, increased circulating levels of the high molecular weight (HMW) multimer of adiponectin may be an important insulin-sensitizing mechanism. We examined the effects of only 21 days of 45 mg of pioglitazone (P+) versus placebo (P-) in nine subjects with type 2 diabetes (HbA(1c), 10.9 +/- 0.6%; BMI, 31.9 +/- 1.5 kg/m(2)). Total adiponectin levels increased by approximately twofold in P+ in association with increased adipose tissue gene expression. However, plasma free fatty acid and glucose levels were unchanged, and there were only minimal changes in other "adipokines." Glucose fluxes ([3-(3)H]glucose infusion) were measured during 6-h euglycemic (5 mmol/l) "pancreatic clamp" studies (somatostatin/glucagon/growth hormone) with stepped insulin levels. Pioglitazone induced marked decreases in endogenous glucose production (P+ = 0.9 +/- 0.1 vs. P- = 1.7 +/- 0.3 mg. kg(-1). min(-1); P < 0.05) at physiologic hyperinsulinemia ( approximately 50 microU/ml), which was highly correlated with an increased ratio of HMW adiponectin/total levels (r(2) = 0.90). Maximal insulin stimulation ( approximately 400 microU/ml) revealed pioglitazone-associated increases in glucose uptake (P+ = 10.5 +/- 0.9 vs. P- = 8.9 +/- 0.8 mg. kg(-1). min(-1); P < 0.05), which did not correlate with HMW or total adiponectin levels. Thus, only 21 days of pioglitazone therapy improved insulin action in humans with type 2 diabetes. Increased abundance of the HMW adiponectin multimer may contribute to the hepatic insulin-sensitizing effects of these agents.
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Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Péptidos y Proteínas de Señalización Intercelular , Tiazolidinedionas/uso terapéutico , Adiponectina , Tejido Adiposo/metabolismo , Citocinas/sangre , Diabetes Mellitus Tipo 2/metabolismo , Sinergismo Farmacológico , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Leptina/sangre , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Pioglitazona , Proteínas/metabolismoRESUMEN
Increased circulating free fatty acids (FFAs) inhibit both hepatic and peripheral insulin action. Because the loss of effectiveness of glucose to suppress endogenous glucose production and stimulate glucose uptake contributes importantly to fasting hyperglycemia in type 2 diabetes, we examined whether the approximate twofold elevations in FFA characteristic of poorly controlled type 2 diabetes contribute to this defect. Glucose levels were raised from 5 to 10 mmol/l while maintaining fixed hormonal conditions by infusing somatostatin with basal insulin, glucagon, and growth hormone. Each individual was studied at two FFA levels: with (NA+) and without (NA-) infusion of nicotinic acid in nine individuals with poorly controlled type 2 diabetes (HbA(1c) = 10.1 +/- 0.7%) and with (LIP+) and without (LIP-) infusion of lipid emulsion in nine nondiabetic individuals. Elevating FFA to approximately 500 micro mol/l blunted the ability of glucose to suppress endogenous glucose production (LIP- = -48% vs. LIP+ = -28%; P < 0.01) and increased glucose uptake (LIP- = 97% vs. LIP+ = 51%; P < 0.01) in nondiabetic individuals. Raising FFA also blunted the endogenous glucose production response in 10 individuals with type 2 diabetes in good control (HbA(1c) = 6.3 +/- 0.3%). Conversely, normalizing FFA nearly restored the endogenous glucose production (NA- = -7% vs. NA+ = -41%; P < 0.001) and glucose uptake (NA- = 26% vs. NA+ = 64%; P < 0.001) responses to hyperglycemia in individuals with poorly controlled type 2 diabetes. Thus, increased FFA levels contribute substantially to the loss of glucose effectiveness in poorly controlled type 2 diabetes.
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Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Ácidos Grasos no Esterificados/sangre , Biomarcadores/sangre , Emulsiones , Técnica de Clampeo de la Glucosa , Prueba de Tolerancia a la Glucosa , Hemoglobina Glucada/análisis , Homeostasis , Humanos , Cinética , Persona de Mediana Edad , Niacina/farmacología , Valores de Referencia , Factores de TiempoRESUMEN
Presentamos a un paciente de sexo feminino, de 18 años, primigesta, con hiperemesis gravídica, deshidratada, que no presentaba hiponatremia. La paciente desarolló nistagmus multidireccional, desorientación temporoesdpacial, apatía y marcha atáxica luego de la admisión al hospital; cuadro compatible con encefalopatía de wernicke. El laboratorio demostraba hipocaliemia, hipernatremia y aumento de las aminotransferasas. La osmolaridad plasmática calculada fue 319 mOsm/Kg y el déficit de agua de 2.73 I. Evolucionó con pérdida de la fuerza en cuatro miembros, hipotoncidad, reflejos tendinosos ausentes y signo de Babinski bilateral. En la resonancia magnética nuclear de cerebro se observaba, en cortes sagitales, una imagen hiperintensa en T2 a nivel pontino y en cortes axiales una banda central hipointensa en T1 sugestivas de mielinolisis central pontina. En el caso de nuestra paciente la mielinosis central pontina probablemente resulta secundaria a la asociación de: hipernatremia, hipersomolaridad de hipocaliemia.