RESUMEN
BACKGROUND Patients with high-acuity liver failure have increased access to marginal and split liver options, owing to historically high waitlist mortality rates. While most research states that donor liver quality has no impact on patients with high-acuity illness, there have been inconsistencies in recent research on how liver quality impacts post-transplant outcomes for these patients. We aimed to quantify donor liver quality with various post-transplantation patient outcomes for patients with high-acuity illness. MATERIAL AND METHODS Using the liver donor risk index (LDRI), model for end stage liver disease (MELD), and clinically relevant recipient factors, we used multivariate logistic regression to analyze how donor liver quality affects varying measures of patient outcomes for 9923 high-acuity patients from June 18, 2013, to June 18, 2022. RESULTS Using LDRI, high-quality livers had a significant protective impact on high-acuity patient mortality, compared with low-quality livers (OR=0.695 [0.549, 0.879], P=0.002). High-quality livers also had significant impact on graft survival (OR=0.706 [0.558, 0.894], P=0.004). Two sensitivity patient mortality analyses, excluding patients with status 1A and hepatocellular carcinoma, showed significant protective findings for high-quality livers. High-quality livers had insignificant outcomes on long-term survivor mortality, length of hospitalization, and primary non-function outcomes, compared with low-quality donor livers. CONCLUSIONS While our findings suggest donor quality has an impact on high-acuity patient outcomes, these findings indicate further research is needed in intent-to-treat analysis on clinical offer data to provide a clearer finding of how donor quality affects patients with high-acuity illness.
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Enfermedad Hepática en Estado Terminal , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Enfermedad Hepática en Estado Terminal/cirugía , Donadores Vivos , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
The liver donor risk index (LDRI) was developed by Feng et al to predict the quality of donor liver allografts. However, there is currently no literature documenting the application and efficacy of Feng's LDRI specifically for the pediatric population. The goal of our study is to apply Feng's LDRI to our study population as well as develop a pediatric-specific LDRI. De-identified data from the United Network for Organ Sharing for 7836 recipients with pediatric transplant were retrospectively analyzed from January 1, 2000, to July 1, 2022. We performed a univariate and multivariate Cox regression analysis to determine the significant recipient and transplant factors impacting pediatric liver allograft survival. These significant factors were used to construct the pediatric-specific LDRI index. Receiver operator characteristic curve analysis was utilized to compare the pediatric-specific and Feng LDRI indexes at 1, 5, and 10 years.ââ Our pediatric-specific LDRI includes 4 variables found to be significant in pediatric populations: donor age: 35-50, ≥ 50; cold ischemia time ≤ 6, and aspartate aminotransferase level > 1000. In addition, our pediatric-specific LDRI had a higher receiver operator characteristic c -statistic compared to Feng's LDRI at 1 year (0.57 vs. 0.55), 5 years (0.57 vs. 0.50), and 10 years (0.58 vs. 0.47). Our findings indicate that there is a need to create a pediatric-specific LDRI as the Feng LDRI has not been shown to be efficacious in pediatric populations. Our index may serve as a starting point for the development of a comprehensive pediatric LDRI.
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Trasplante de Hígado , Humanos , Niño , Adulto , Persona de Mediana Edad , Trasplante de Hígado/efectos adversos , Estudios Retrospectivos , Donadores Vivos , Donantes de Tejidos , Hígado , Análisis Multivariante , Supervivencia de Injerto , Receptores de Trasplantes , Factores de RiesgoRESUMEN
OBJECTIVE: Pulsatile insulin secretion is impaired in diseases such as type 2 diabetes that are characterized by insulin resistance. This has led to the suggestion that changes in insulin pulsatility directly impair insulin signaling. We sought to examine the effects of pulse characteristics on insulin action in humans, hypothesizing that a decrease in pulse amplitude or frequency is associated with impaired hepatic insulin action. METHODS: We studied 29 nondiabetic subjects on two occasions. On 1 occasion, hepatic and peripheral insulin action was measured using a euglycemic clamp. The deuterated water method was used to estimate the contribution of gluconeogenesis to endogenous glucose production. On a separate study day, we utilized nonparametric stochastic deconvolution of frequently sampled peripheral C-peptide concentrations during fasting to reconstruct portal insulin secretion. In addition to measuring basal and pulsatile insulin secretion, we used approximate entropy to measure orderliness and Fourier transform to measure the average, and the dispersion of, insulin pulse frequencies. RESULTS: In univariate analysis, basal insulin secretion (R2â =â 0.16) and insulin pulse amplitude (R2â =â 0.09) correlated weakly with insulin-induced suppression of gluconeogenesis. However, after adjustment for age, sex, and weight, these associations were no longer significant. The other pulse characteristics also did not correlate with the ability of insulin to suppress endogenous glucose production (and gluconeogenesis) or to stimulate glucose disappearance. CONCLUSIONS: Overall, our data demonstrate that insulin pulse characteristics, considered independently of other factors, do not correlate with measures of hepatic and peripheral insulin sensitivity in nondiabetic humans.
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Glucosa/metabolismo , Secreción de Insulina/fisiología , Insulina/metabolismo , Adulto , Glucemia/metabolismo , Péptido C/metabolismo , Ayuno/fisiología , Femenino , Gluconeogénesis/fisiología , Técnica de Clampeo de la Glucosa , Humanos , Resistencia a la Insulina/fisiología , Hígado/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUNDMetabolic disorders such as type 2 diabetes have been associated with a decrease in insulin pulse frequency and amplitude. We hypothesized that the T allele at rs7903146 in TCF7L2, previously associated with ß cell dysfunction, would be associated with changes in these insulin pulse characteristics.METHODSTwenty-nine nondiabetic subjects (age 46 ± 2, BMI 28 ± 1 kg/m2) participated in this study. Of these, 16 were homozygous for the C allele at rs7903146 and 13 were homozygous for the T allele. Deconvolution of peripheral C-peptide concentrations allowed the reconstruction of portal insulin secretion over time. These data were used for subsequent analyses. Pulse orderliness was assessed by approximate entropy (ApEn), and the dispersion of insulin pulses was measured by a frequency dispersion index (FDI) after a Fast Fourier Transform (FFT) of individual insulin secretion rates.RESULTSDuring fasting conditions, the CC genotype group exhibited decreased pulse disorderliness compared with the TT genotype group (1.10 ± 0.03 vs. 1.19 ± 0.04, P = 0.03). FDI decreased in response to hyperglycemia in the CC genotype group, perhaps reflecting less entrainment of insulin secretion during fasting.CONCLUSIONDiabetes-associated variation in TCF7L2 is associated with decreased orderliness and pulse dispersion, unchanged by hyperglycemia. Quantification of ApEn and FDI could represent novel markers of ß cell health.FUNDINGThis work was funded by US NIH (DK78646, DK116231), University of Padova research grant CPDA145405, and Mayo Clinic General Clinical Research Center (UL1 TR000135).
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Alelos , Diabetes Mellitus Tipo 2/genética , Secreción de Insulina/genética , Polimorfismo Genético , Proteína 2 Similar al Factor de Transcripción 7/genética , Adulto , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Células Secretoras de Insulina/metabolismo , Masculino , Persona de Mediana Edad , Proteína 2 Similar al Factor de Transcripción 7/metabolismoAsunto(s)
Insuficiencia Suprarrenal/inducido químicamente , Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Hiponatremia/inducido químicamente , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Neoplasias Pulmonares/tratamiento farmacológico , Insuficiencia Suprarrenal/fisiopatología , Caquexia/fisiopatología , Femenino , Humanos , Hiponatremia/fisiopatología , Persona de Mediana Edad , Debilidad Muscular/fisiopatologíaAsunto(s)
Angioedema/inducido químicamente , Antagonistas de Receptores de Angiotensina/efectos adversos , Úvula , Angioedema/diagnóstico por imagen , Angioedema/tratamiento farmacológico , Diagnóstico Diferencial , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: To report a case of severe hypercalcemia, exacerbated by vitamin A supplementation and hydrochlorothiazide, in a patient with primary hyperparathyroidism. METHODS: Clinical and laboratory findings are presented along with response to therapy. RESULTS: A 68-year-old white female presented to the emergency department complaining of nausea, vomiting, and altered mental status. Laboratory findings revealed calcium 15.8 mg/dL (8.4-10.2), albumin 4.1 g/dL (3.8-4.8), and parathyroid hormone 62 pg/mL (14-64). Serum calcium improved after intravenous hydration with normal saline. Prior to this hospitalization, over-the-counter medications were significant for calcium (600 mg daily), vitamin A (11 000 IU daily), and vitamin D (800 IU daily).The patient's prescription medications were significant for hydrochlorothiazide (12.5 mg daily). Twenty-four-hour urine calcium was subsequently found to be 146 mg (35-250). Myeloma, lymphoma, and sarcoidosis were ruled out as the etiology for hypercalcemia. The diagnosis of primary hyperparathyroidism was confirmed. She was treated surgically for primary hyperparathyroidism. The right and left superior parathyroid showed hypercellular parathyroid on pathology. The patient was normocalcemic after surgery. CONCLUSION: Previous reports suggest that very high doses of vitamin A is required to cause hypercalcemia. This case suggests that in a setting of primary hyperparathyroidism and hydrochlorothiazide therapy, vitamin A may contribute to the development of severe hypercalcemia in patients who are on calcium and vitamin D supplements. Given their biologic effects, public awareness needs to be created regarding the injudicious use of vitamins.
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Hidroclorotiazida/efectos adversos , Hipercalcemia/inducido químicamente , Hiperparatiroidismo Primario/diagnóstico , Vitamina A/efectos adversos , Anciano , Calcio/administración & dosificación , Calcio/efectos adversos , Suplementos Dietéticos/efectos adversos , Femenino , Humanos , Hiperparatiroidismo Primario/sangre , Hiperparatiroidismo Primario/cirugía , Hormona Paratiroidea/sangre , Vitamina D/efectos adversosRESUMEN
The characteristics of pulsatile insulin secretion are important determinants of type 2 diabetes pathophysiology, but they are understudied due to the difficulties in measuring pulsatile insulin secretion noninvasively. Deconvolution of either peripheral C-peptide or insulin concentrations offers an appealing alternative to hepatic vein catheterization. However, to do so, there are a series of methodological challenges to overcome. C-peptide has a relatively long half-life and accumulates in the circulation. On the other hand, peripheral insulin concentrations reflect relatively fast clearance and hepatic extraction as it leaves the portal circulation to enter the systemic circulation. We propose a method based on nonparametric stochastic deconvolution of C-peptide concentrations, using individually determined C-peptide kinetics, to overcome these limitations. The use of C-peptide (instead of insulin) concentrations allows estimation of portal (and not post-hepatic) insulin pulses, whereas nonparametric stochastic deconvolution allows evaluation of pulsatile signals without any a priori assumptions of pulse shape and occurrence. The only assumption required is the degree of smoothness of the (unknown) secretion rate. We tested this method first on simulated data and then on 29 nondiabetic subjects studied during euglycemia and hyperglycemia and compared our estimates with the profiles obtained from hepatic vein insulin concentrations. This method produced satisfactory results both in the ability to fit the data and in providing reliable estimates of pulsatile secretion, in agreement with hepatic vein measurements. In conclusion, the proposed method enables reliable and noninvasive measurement of pulsatile insulin secretion. Future studies will be needed to validate this method in people with type 2 diabetes.
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Péptido C/sangre , Hiperglucemia/sangre , Secreción de Insulina/fisiología , Insulina/sangre , Adulto , Péptido C/metabolismo , Simulación por Computador , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Glucosa/metabolismo , Voluntarios Sanos , Venas Hepáticas , Humanos , Hiperglucemia/metabolismo , Insulina/metabolismo , Cinética , Masculino , Persona de Mediana Edad , Estadísticas no ParamétricasRESUMEN
AIMS: To compare the performance of population-based kinetics with that of directly measured C-peptide kinetics when used to calculate ß-cell responsivity indices, and to study people with and without acute insulin resistance to ensure that population-based kinetics apply to all conditions where ß-cell function is measured. METHODS: Somatostatin was used to inhibit endogenous insulin secretion in 56 people without diabetes. Subsequently, a C-peptide bolus was administered and the changing concentrations were used to calculate individual kinetic measures of C-peptide clearance. In addition, the participants were studied on 2 occasions in random order using an oral glucose tolerance test (OGTT). On one occasion, free fatty acid elevation, to cause insulin resistance, was achieved by infusion of Intralipid + heparin. The Disposition Index (DI) was then estimated by the oral minimal model using either population-based or individual C-peptide kinetics. RESULTS: There were marked differences in the exchange variables (k 12 and k 21 ) of the model describing C-peptide kinetics, but smaller differences in the fractional clearance; that is, the irreversible loss from the accessible compartment (k 01 ), obtained from population-based estimates compared with experimental measurement. Because it is predominantly influenced by k 01 , DI estimated using individual kinetics correlated well with DI estimated using population-based kinetics. CONCLUSIONS: These data support the use of population-based measures of C-peptide kinetics to estimate ß-cell function during an OGTT.
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Péptido C/metabolismo , Diabetes Mellitus Tipo 2/fisiopatología , Resistencia a la Insulina/fisiología , Células Secretoras de Insulina/fisiología , Femenino , Glucosa/farmacología , Prueba de Tolerancia a la Glucosa , Glicerol/farmacología , Hormonas/farmacología , Humanos , Masculino , Persona de Mediana Edad , Solventes/farmacología , Somatostatina/farmacología , Edulcorantes/farmacologíaRESUMEN
Context: Abnormal glucagon concentrations contribute to hyperglycemia, but the mechanisms of α-cell dysfunction in prediabetes are unclear. Objective: We sought to determine the relative contributions of insulin secretion and action to α-cell dysfunction in nondiabetic participants across the spectrum of glucose tolerance. Design: This was a cross-sectional study. A subset of participants (n = 120) was studied in the presence and absence of free fatty acid (FFA) elevation, achieved by infusion of Intralipid (Baxter Healthcare, Deerfield, IL) plus heparin, to cause insulin resistance. Setting: An inpatient clinical research unit at an academic medical center. Participants: A total of 310 nondiabetic persons participated in this study. Interventions: Participants underwent a seven-sample oral glucose tolerance test. Subsequently, 120 participants were studied on two occasions. On one day, infusion of Intralipid plus heparin raised FFA. On the other day, participants received glycerol as a control. Main Outcome Measure(s): We examined the relationship of glucagon concentration with indices of insulin action after adjusting for the effects of age, sex, and weight. Subsequently, we sought to determine whether an acute decrease in insulin action, produced by FFA elevation, altered glucagon concentrations in nondiabetic participants. Results: Fasting glucagon concentrations correlated positively with fasting insulin and C-peptide concentrations and inversely with insulin action. Fasting glucagon was not associated with any index of ß-cell function in response to an oral challenge. As expected, FFA elevation decreased insulin action and also raised glucagon concentrations. Conclusions: In nondiabetic participants, glucagon secretion was altered by changes in insulin action.
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Células Secretoras de Glucagón/patología , Glucagón/sangre , Hiperglucemia/fisiopatología , Resistencia a la Insulina , Insulina/farmacología , Estado Prediabético/fisiopatología , Biomarcadores/sangre , Glucemia/metabolismo , Péptido C/sangre , Estudios Transversales , Femenino , Estudios de Seguimiento , Células Secretoras de Glucagón/efectos de los fármacos , Células Secretoras de Glucagón/metabolismo , Prueba de Tolerancia a la Glucosa , Humanos , Hipoglucemiantes/farmacología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
AIMS/HYPOTHESIS: Shift-work is associated with circadian rhythm disruption and an increased risk of obesity and type 2 diabetes. We sought to determine the effect of rotational shift-work on glucose metabolism in humans. METHODS: We studied 12 otherwise healthy nurses performing rotational shift-work using a randomised crossover study design. On each occasion, participants underwent an isotope-labelled mixed meal test during a simulated day shift and a simulated night shift, enabling simultaneous measurement of glucose flux and beta cell function using the oral minimal model. We sought to determine differences in fasting and postprandial glucose metabolism during the day shift vs the night shift. RESULTS: Postprandial glycaemic excursion was higher during the night shift (381±33 vs 580±48 mmol/l per 5 h, p<0.01). The time to peak insulin and C-peptide and nadir glucagon suppression in response to meal ingestion was also delayed during the night shift. While insulin action did not differ between study days, the beta cell responsivity to glucose (59±5 vs 44±4 × 10-9 min-1; p<0.001) and disposition index were decreased during the night shift. CONCLUSIONS/INTERPRETATION: Impaired beta cell function during the night shift may result from normal circadian variation, the effect of rotational shift-work or a combination of both. As a consequence, higher postprandial glucose concentrations are observed during the night shift.
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Glucemia/metabolismo , Glucagón/metabolismo , Adulto , Péptido C/metabolismo , Ritmo Circadiano/fisiología , Estudios Cruzados , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Personal de Salud , Humanos , Insulina/metabolismo , Masculino , Periodo Posprandial , Horario de Trabajo por Turnos , Adulto JovenRESUMEN
OBJECTIVE: TCF7L2 variant rs7903146 is associated with increased risk for type 2 diabetes. We investigated the effect of TCF7L2 variant rs7903146 and glucose tolerance on free fatty acid (FFA) metabolism. RESEARCH DESIGN AND METHODS: We recruited 120 individuals, half homozygous for the major CC allele and half homozygous for the minor TT allele at rs7903146; each underwent a 2-h, 75g oral glucose tolerance test (OGTT). Plasma glucose, insulin and free fatty acid concentrations were measured on blood collected before and during the OGTT. RESULTS: Total FFA concentrations and percent FA species during OGTT were not different in CC and TT carriers when males and females were considered together. However, monounsaturated fatty acid (MUFA) concentrations and percentages were greater in TT than CC females during the OGTT. TT carriers with high HOMA-IR had significantly greater fasting FFA concentrations, lower disposition index (DI) and greater AUC of glucose than high HOMA-IR CC carriers, whereas no such differences were observed in the low HOMA-IR group. We found that fasting (826±25 vs. 634±22µmol/L, P<0.0001) and OGTT plasma FFA concentrations were greater in IGT than NGT subjects, and the difference remained after adjusting for sex, age, BMI, and genotype. Finally, IGT subjects had greater MUFA concentrations and percentages than NGT subjects during OGTT. CONCLUSIONS: Despite similar fasting insulin and glucose, fasting plasma FFA are greater in IGT than NGT adults. Insulin resistance and sex influence plasma FFA responses amongst carriers of the minor T allele of TCF7L2 rs7903146.
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Ácidos Grasos no Esterificados/metabolismo , Prueba de Tolerancia a la Glucosa , Proteína 2 Similar al Factor de Transcripción 7/genética , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Adulto , Anciano , Femenino , Variación Genética/genética , Genotipo , Heterocigoto , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
Pregnant women with diabetes may have underlying beta cell dysfunction due to mutations/rare variants in genes associated with Maturity Onset Diabetes of the Young (MODY). MODY gene screening would reveal those women genetically predisposed and previously unrecognized with a monogenic form of diabetes for further clinical management, family screening and genetic counselling. However, there are minimal data available on MODY gene variants in pregnant women with diabetes from India. In this study, utilizing the Next generation sequencing (NGS) based protocol fifty subjects were screened for variants in a panel of thirteen MODY genes. Of these subjects 18% (9/50) were positive for definite or likely pathogenic or uncertain MODY variants. The majority of these variants was identified in subjects with autosomal dominant family history, of whom five were in women with pre-GDM and four with overt-GDM. The identified variants included one patient with HNF1A Ser3Cys, two PDX1 Glu224Lys, His94Gln, two NEUROD1 Glu59Gln, Phe318Ser, one INS Gly44Arg, one GCK, one ABCC8 Arg620Cys and one BLK Val418Met variants. In addition, three of the seven offspring screened were positive for the identified variant. These identified variants were further confirmed by Sanger sequencing. In conclusion, these findings in pregnant women with diabetes, imply that a proportion of GDM patients with autosomal dominant family history may have MODY. Further NGS based comprehensive studies with larger samples are required to confirm these finding.
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Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Pruebas Genéticas/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación/genética , Adulto , Estudios Transversales , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , India/epidemiología , Masculino , Linaje , Fenotipo , EmbarazoRESUMEN
CONTEXT: Prediabetes is a heterogeneous disorder classified on the basis of fasting glucose concentrations and 2-hour glucose tolerance. OBJECTIVE: We sought to determine the relative contributions of insulin secretion and action to the pathogenesis of isolated impaired glucose tolerance (IGT). DESIGN: The study consisted of an oral glucose tolerance test and a euglycemic clamp performed in two cohorts matched for anthropometric characteristics and fasting glucose but discordant for glucose tolerance. SETTING: An inpatient clinical research unit at an academic medical center. PATIENTS OR OTHER PARTICIPANTS: Twenty-five subjects who had normal fasting glucose (NFG) and normal glucose tolerance (NGT) and 19 NFG/IGT subjects participated in this study. INTERVENTION(S): Subjects underwent a seven-sample oral glucose tolerance test and a 4-hour euglycemic, hyperinsulinemic clamp on separate occasions. Glucose turnover during the clamp was measured using tracers, and endogenous hormone secretion was inhibited by somatostatin. MAIN OUTCOME MEASURES: We sought to determine whether hepatic glucose metabolism, specifically the contribution of gluconeogenesis to endogenous glucose production, differed between subjects with NFG/NGT and those with NFG/IGT. RESULTS: Endogenous glucose production did not differ between groups before or during the clamp. Insulin-stimulated glucose disappearance was lower in NFG/IGT (24.6 ± 2.2 vs 35.0 ± 3.6 µmol/kg/min; P = .03). The disposition index was decreased in NFG/IGT (681 ± 102 vs 2231 ± 413 × 10-14 dL/kg/min2 per pmol/L; P < .001). CONCLUSIONS: We conclude that innate defects in the regulation of glycogenolysis and gluconeogenesis do not contribute to NFG/IGT. However, insulin-stimulated glucose disposal is impaired, exacerbating defects in ß-cell function.
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Glucemia/metabolismo , Intolerancia a la Glucosa/metabolismo , Estudios de Cohortes , Femenino , Técnica de Clampeo de la Glucosa , Intolerancia a la Glucosa/sangre , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A common genetic variation in TCF7L2 is associated with type 2 diabetes. However, the mechanism by which this occurs remains elusive. In addition to affecting insulin secretion, genetic variation at the TCF7L2 locus may alter insulin action or directly modify hepatic glucose metabolism. We sought to determine whether the diabetes-associated variant in this locus (the T allele of rs7903146) increases fasting endogenous glucose production (EGP), and impairs insulin-induced suppression of EGP and insulin-stimulated glucose disappearance. To address this, we studied individuals who were either homozygous for the diabetes-associated allele (TT) at rs7903146 or were homozygous for the protective allele (CC). Subjects were matched for other anthropometric characteristics and were studied using a euglycemic clamp. EGP and glucose uptake were measured using the tracer dilution technique, and the relative contribution of gluconeogenesis to EGP was quantitated using deuterated water corrected for transaldolase exchange. We report that the diabetes-associated variation in TCF7L2 did not associate with fasting EGP, insulin-induced suppression of EGP, and insulin-induced stimulation of glucose uptake. There was no association with the contribution of gluconeogenesis and glycogenolysis to EGP. These data indicate that genetic variation at TCF7L2 does not predispose an individual to type 2 diabetes by altering either hepatic or extrahepatic insulin action.
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Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Resistencia a la Insulina/genética , Hígado/metabolismo , Polimorfismo de Nucleótido Simple , Proteína 2 Similar al Factor de Transcripción 7/genética , Adulto , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Técnica de Clampeo de la Glucosa , Humanos , Masculino , Persona de Mediana Edad , Proteína 2 Similar al Factor de Transcripción 7/metabolismoRESUMEN
The diabetes-associated allele in TCF7L2 increases the rate of conversion to diabetes; however, the mechanism by which this occurs remains elusive. We hypothesized that the diabetes-associated allele in this locus (rs7903146) impairs insulin secretion and that this defect would be exacerbated by acute free fatty acid (FFA)-induced insulin resistance. We studied 120 individuals of whom one-half were homozygous for the diabetes-associated allele TT at rs7903146 and one-half were homozygous for the protective allele CC. After a screening examination during which glucose tolerance status was determined, subjects were studied on two occasions in random order while undergoing an oral challenge. During one study day, FFA was elevated by infusion of Intralipid plus heparin. On the other study day, subjects received the same amount of glycerol as present in the Intralipid infusion. ß-Cell responsivity indices were estimated with the oral C-peptide minimal model. We report that ß-cell responsivity was slightly impaired in the TT genotype group. Moreover, the hyperbolic relationship between insulin secretion and ß-cell responsivity differed significantly between genotypes. Subjects also exhibited impaired suppression of glucagon after an oral challenge. These data imply that a genetic variant harbored within the TCF7L2 locus impairs glucose tolerance through effects on glucagon as well as on insulin secretion.
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Alelos , Diabetes Mellitus/genética , Células Secretoras de Glucagón/fisiología , Células Secretoras de Insulina/efectos de los fármacos , Proteína 2 Similar al Factor de Transcripción 7/genética , Adulto , Anciano , Estudios de Cohortes , Emulsiones/farmacología , Ácidos Grasos no Esterificados/metabolismo , Femenino , Variación Genética , Genotipo , Glucagón/metabolismo , Prueba de Tolerancia a la Glucosa , Glicerol/farmacología , Humanos , Insulina/metabolismo , Resistencia a la Insulina/genética , Secreción de Insulina , Células Secretoras de Insulina/fisiología , Masculino , Persona de Mediana Edad , Fosfolípidos/farmacología , Aceite de Soja/farmacologíaRESUMEN
BACKGROUND: Although there are reports describing the association of alternations of bone and mineral metabolism in epileptic patients with long-term anticonvulsant therapy, there are only limited Indian studies which have looked at this aspect. OBJECTIVES: This study was done to compare the prevalence of changes in bone mineral parameters and bone mineral density (BMD) in ambulant individuals on long-term anticonvulsant therapy with age- and body mass index (BMI)-matched healthy controls. MATERIALS AND METHODS: There were 55 men (on medications for more than 6 months) and age- and BMI-matched 53 controls. Drug history, dietary calcium intake (DCI), and duration of sunlight exposure were recorded. Bone mineral parameters and BMD were measured. RESULTS: The control group had a significantly higher daily DCI with mean ± SD of 396 ± 91 mg versus 326 ± 101 mg (P = 0.007) and more sunlight exposure of 234 ± 81 vs 167 ± 69 min (P = 0.05). BMD at the femoral neck was significantly lower in cases (0.783 ± 0.105 g/cm(2)) when compared to controls (0.819 ± 0.114 g/cm(2)). Majority of the patients (61%) had low femoral neck BMD (P = 0.04). There was no significant difference in the proportion of subjects with vitamin D deficiency (<20 ng/mL) between cases (n = 32) and controls (n = 37) (P = 0.234). CONCLUSIONS: Vitamin D deficiency was seen in both the groups in equal proportions, highlighting the existence of a high prevalence of this problem in India. Low femoral neck BMD found in cases may stress the need for supplementing calcium and treating vitamin D deficiency in this specific group. However, the benefit of such intervention has to be studied in a larger proportion of epileptic patients.
RESUMEN
BACKGROUND: Hypertension is one of the most important determinants of death due to vascular damage and is fast emerging as a high burden disease in India. However, its documentation is poor in the country. This study aims to estimate the rate and the causal pattern of mortality in a cohort of people with high blood pressure as compared to normotensives. METHODS: The study setting is Varkkala, a rural village in southern Kerala, India, and the study design was that of a prospective cohort. A total of 77,881 participants of age 20 years and above were considered for analysis. The rate and risk of all cause mortality (death due to any cause) among hypertensives were quantified and compared against the normotensives. The causes of death were also analyzedin both the groups. Cox proportional hazard models were created to estimate the hazard ratios of death among hypertensives adjusted for sociodemographic factors, behaviors, and comorbidities. RESULTS: The incidence proportion of deaths in the study was 4.28% during the follow-up period of 6 years. The relative risk of mortality was 3.13 (CI: 2.91-3.37) in the high BP group. The age-adjusted hazard ratio of all cause mortality for the high BP group was 2.96 (2.56-3.42). Coronary artery disease was the major cause of death among the subjects with high BP. CONCLUSIONS: The study revealed high prevalence of hypertension in the study population. A person with hypertension is at three times higher risk of death due to any cause compared to a normotensive individual even after adjustment for age.
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Ferroelectric-germanium heterostructures have a strong potential for multifunctional devices. Germanium (Ge) is attractive due to its higher electron and hole mobilities while ferroelectric BaTiO3 is promising due to its high relative permittivity, which can make next-generation low-voltage and low-leakage metal-oxide semiconductor field-effect transistors. Here, we investigate the growth, structural, chemical, and band alignment properties of pulsed laser deposited BaTiO3 on epitaxial (100)Ge, (110)Ge, and (111)Ge layers. Cross-sectional transmission electron microscopy micrographs show the amorphous nature of the BaTiO3 layer and also show a sharp heterointerface between BaTiO3 and Ge. The appearance of strong Pendellösung oscillation fringes from high-resolution X-ray diffraction implies the presence of parallel and sharp heterointerfaces. The valence band offset relation of ΔEV(100) ≥ ΔEV(111) > ΔEV(110) and the conduction band offset relation of ΔE(C)(110) > ΔE(C)(111) ≥ ΔE(C)(100) on crystallographically oriented Ge offer significant advancement for designing new-generation ferroelectric-germanium-based multifunctional devices.