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1.
Am J Med Genet A ; 179(7): 1362-1365, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31059209

RESUMEN

Fetal akinesia deformation sequence (FADS) and lethal multiple pterygium syndrome (LMPS) are clinically overlapping syndromes manifesting with reduced or absent fetal movement, arthrogryposis, and several anomalies during fetal life. The etiology of these syndromes is heterogeneous, and in many cases it remains unknown. In order to determine the genetic etiology of FADS in two fetuses with fetal akinesia, arthrogryposis, edema, and partial cleft palate, we utilized exome sequencing. Our investigations revealed a homozygous nonsense variant [c.1116C>A, p.(Cys372Ter)] in the SLC18A3 gene, which encodes for the vesicular acetylcholine transporter (VAChT) responsible for active transport of acetylcholine in the neuromuscular junction. This is the first description of a nonsense variant in the SLC18A3 gene, as only missense variants and whole gene deletions have been previously identified in patients. The previously detected SLC18A3 defects have been associated with congenital myasthenic syndromes, and therefore our findings extend the clinical spectrum of SLC18A3 defects to severe prenatal phenotypes. Our findings suggest that nonsense variants in SLC18A3 cause a more severe phenotype than missense variants and are in line with previous studies showing a lethal phenotype in VAChT knockout mice. Our results underline the importance of including SLC18A3 sequencing in the differential diagnostics of fetuses with arthrogryposis, FADS, or LMPS of unknown etiology.


Asunto(s)
Artrogriposis , Mutación Missense , Proteínas de Transporte Vesicular de Acetilcolina/genética , Animales , Femenino , Humanos , Ratones , Ratones Noqueados , Embarazo
2.
Eur J Pediatr ; 174(12): 1689-92, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26070998

RESUMEN

We report a fetal case with fatal outcome having a novel mutation in the HADHB gene, coding the beta-subunit of the mitochondrial trifunctional protein. Parents had a previous pregnancy loss due to fetal heart failure and hydrops. The next pregnancy led to left ventricular noncompaction and increasing pleural effusions after 29 gestational weeks. The fetus was small for gestational age, and long bones were abnormally short. The baby was born severely asphyxiated at 32 gestational weeks by cesarean section. Intensive care was withdrawn due to failure to thrive and suspicion of a severe mitochondrial disorder. Postmortem brain MRI suggested microcephaly with a simplified gyral pattern. The lateral cerebral ventricles were normal. Chromosome analysis was normal (46, XX). Fibroblasts cultured from a skin biopsy of the baby revealed the large homozygous deletion c.1109+243_1438-703del in the HADHB gene, and heterozygous mutations were detected in both parents. The deletion has not been reported earlier. CONCLUSION: It is important to differentiate systemic metabolic diseases from disorders that affect only the cardiac muscle. Trifunctional protein deficiency is a relatively rare disorder of the fatty acid ß-oxidation cycle. The mutation in the HADHB gene causes a systemic disease with early-onset cardiomyopathy. Understanding the molecular genetic defect of the patient allows appropriate genetic counseling of the family. WHAT IS KNOWN: • Mitochondrial disorders as a group are an important etiology for fetal cardiomyopathies including human trifunctional protein (TFP) disorders and several other mitochondrial diseases. WHAT IS NEW: • We report a fetal case with fatal outcome having a novel mitochondrial trifunctional protein mutation (c.1109+243_1438-703del in the HADHB gene).


Asunto(s)
Cardiomiopatías/genética , Ventrículos Cardíacos/anomalías , Errores Innatos del Metabolismo Lipídico/genética , Miopatías Mitocondriales/genética , Subunidad beta de la Proteína Trifuncional Mitocondrial/genética , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso/genética , Rabdomiólisis/genética , Adulto , Cardiomiopatías/diagnóstico , Ecocardiografía , Resultado Fatal , Femenino , Enfermedades Fetales , Feto , Humanos , Errores Innatos del Metabolismo Lipídico/diagnóstico , Miopatías Mitocondriales/diagnóstico , Proteína Trifuncional Mitocondrial/genética , Mutación , Enfermedades del Sistema Nervioso/diagnóstico , Embarazo , Rabdomiólisis/diagnóstico
3.
J Clin Invest ; 124(9): 3891-900, 2014 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-25133425

RESUMEN

Appropriate development of stratified, squamous, keratinizing epithelia, such as the epidermis and oral epithelia, generates an outer protective permeability barrier that prevents water loss, entry of toxins, and microbial invasion. During embryogenesis, the immature ectoderm initially consists of a single layer of undifferentiated, cuboidal epithelial cells that stratifies to produce an outer layer of flattened periderm cells of unknown function. Here, we determined that periderm cells form in a distinct pattern early in embryogenesis, exhibit highly polarized expression of adhesion complexes, and are shed from the outer surface of the embryo late in development. Mice carrying loss-of-function mutations in the genes encoding IFN regulatory factor 6 (IRF6), IκB kinase-α (IKKα), and stratifin (SFN) exhibit abnormal epidermal development, and we determined that mutant animals exhibit dysfunctional periderm formation, resulting in abnormal intracellular adhesions. Furthermore, tissue from a fetus with cocoon syndrome, a lethal disorder that results from a nonsense mutation in IKKA, revealed an absence of periderm. Together, these data indicate that periderm plays a transient but fundamental role during embryogenesis by acting as a protective barrier that prevents pathological adhesion between immature, adhesion-competent epithelia. Furthermore, this study suggests that failure of periderm formation underlies a series of devastating birth defects, including popliteal pterygium syndrome, cocoon syndrome, and Bartsocas-Papas syndrome.


Asunto(s)
Desarrollo Embrionario , Epidermis/embriología , Proteínas 14-3-3/fisiología , Animales , Adhesión Celular , Polaridad Celular , Ectodermo/embriología , Células Epidérmicas , Epitelio/embriología , Epitelio/fisiología , Humanos , Quinasa I-kappa B/fisiología , Factores Reguladores del Interferón/fisiología , Ratones , Mutación
4.
Hum Mutat ; 33(2): 316-26, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22095942

RESUMEN

Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.


Asunto(s)
Genes Recesivos , Mutación , Sistema Renina-Angiotensina/genética , Anomalías Urogenitales/genética , Angiotensinógeno/genética , Animales , Modelos Animales de Enfermedad , Estudios de Asociación Genética , Humanos , Túbulos Renales Proximales/anomalías , Peptidil-Dipeptidasa A/genética , Receptor de Angiotensina Tipo 1/genética , Renina/genética , Anomalías Urogenitales/diagnóstico
5.
N Engl J Med ; 363(17): 1631-7, 2010 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-20961246

RESUMEN

We report an autosomal recessive lethal syndrome characterized by multiple fetal malformations, the most obvious anomalies being the defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin. We identified the molecular defect that causes this syndrome, using a combined strategy of gene-expression arrays, candidate-gene analysis, clinical studies, and genealogic investigations. A point mutation in two affected fetuses led to the loss of the conserved helix­loop­helix ubiquitous kinase (CHUK), also known as IκB kinase α. CHUK has an essential role in the development of skin epidermis and its derivatives, along with various other morphogenetic events. (Funded by the Academy of Finland and others.).


Asunto(s)
Anomalías Múltiples/genética , Cara/anomalías , Quinasa I-kappa B/genética , Deformidades Congénitas de las Extremidades/genética , Mutación Puntual , Animales , Expresión Génica , Genes Recesivos , Humanos , Ratones , Ratones Noqueados/genética , Linaje
6.
J Clin Endocrinol Metab ; 95(11): E373-83, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20685857

RESUMEN

CONTEXT: AIP mutations (AIPmut) give rise to a pituitary adenoma predisposition that occurs in familial isolated pituitary adenomas and less often in sporadic cases. The clinical and therapeutic features of AIPmut-associated pituitary adenomas have not been studied comprehensively. OBJECTIVE: The objective of the study was to assess clinical/therapeutic characteristics of AIPmut pituitary adenomas. DESIGN: This study was an international, multicenter, retrospective case collection/database analysis. SETTING: The study was conducted at 36 tertiary referral endocrine and clinical genetics departments. PATIENTS: Patients included 96 patients with germline AIPmut and pituitary adenomas and 232 matched AIPmut-negative acromegaly controls. RESULTS: The AIPmut population was predominantly young and male (63.5%); first symptoms occurred as children/adolescents in 50%. At diagnosis, most tumors were macroadenomas (93.3%); extension and invasion was common. Somatotropinomas comprised 78.1% of the cohort; there were also prolactinomas (n = 13), nonsecreting adenomas (n = 7), and a TSH-secreting adenoma. AIPmut somatotropinomas were larger (P = 0.00026), with higher GH levels (P = 0.00068), more frequent extension (P = 0.018) and prolactin cosecretion (P = 0.00023), and occurred 2 decades before controls (P < 0.000001). Gigantism was more common in the AIPmut group (P < 0.000001). AIPmut somatotropinoma patients underwent more surgical interventions (P = 0.00069) and had lower decreases in GH (P = 0.00037) and IGF-I (P = 0.028) and less tumor shrinkage with somatostatin analogs (P < 0.00001) vs. controls. AIPmut prolactinomas occurred generally in young males and frequently required surgery or radiotherapy. CONCLUSIONS: AIPmut pituitary adenomas have clinical features that may negatively impact treatment efficacy. Predisposition for aggressive disease in young patients, often in a familial setting, suggests that earlier diagnosis of AIPmut pituitary adenomas may have clinical utility.


Asunto(s)
Adenoma/genética , Mutación de Línea Germinal , Neoplasias Hipofisarias/genética , Adenoma/patología , Adenoma/terapia , Factores de Edad , Agonistas de Dopamina/uso terapéutico , Femenino , Humanos , Masculino , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/terapia , Resultado del Tratamiento
7.
Genet Med ; 9(10): 690-4, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-18073582

RESUMEN

PURPOSE: Autosomal dominant CHARGE syndrome (OMIM no. 214800) is characterized by choanal atresia or cleft lip or palate, ocular colobomas, cardiovascular malformations, retardation of growth, ear anomalies, and deafness, and is caused by mutations in the CHD7 gene. Here, we describe the outcome of a molecular genetic analysis in 18 Finnish and 56 German patients referred for molecular confirmation of the clinical diagnosis of suspected CHARGE syndrome. METHODS: Quantitative real-time polymerase chain reaction or multiplex ligation-dependent probe amplification assays did not reveal deletions in mutation negative cases, suggesting that larger CHD7 deletions are not a major cause of CHARGE syndrome. RESULTS: In this group of 74 patients, we found mutations in 30 cases. 22 mutations were novel, including 11 frameshift, 5 nonsense, 3 splice-site, and 3 missense mutations. One de novo frameshift mutation was found in the last exon and is expected to result in a minimally shortened CHD7 polypeptide. Because the mutation is associated with a typical CHARGE syndrome phenotype, it may indicate the presence of an as yet unknown functional domain in the very carboxyterminal end of CHD7. CONCLUSIONS: Our mutation detection rate of 40.5% is reflective of screening an unselected sample population referred for CHD7 testing based on suspected clinical diagnosis of CHARGE syndrome and not for having met strict clinical criteria for this disorder.


Asunto(s)
Anomalías Múltiples/genética , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Eliminación de Gen , Mutación , Adolescente , Adulto , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Reacción en Cadena de la Polimerasa , Síndrome
9.
PLoS Med ; 2(12): e345, 2005 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-17570749

RESUMEN

BACKGROUND: Type 2 diabetes (T2D) is a multifactorial disease in which environmental triggers interact with genetic variants in the predisposition to the disease. A number of common variants have been associated with T2D but our knowledge of their ability to predict T2D prospectively is limited. METHODS AND FINDINGS: By using a Cox proportional hazard model, common variants in the PPARG (P12A), CAPN10 (SNP43 and 44), KCNJ11 (E23K), UCP2 (-866G>A), and IRS1 (G972R) genes were studied for their ability to predict T2D in 2,293 individuals participating in the Botnia study in Finland. After a median follow-up of 6 y, 132 (6%) persons developed T2D. The hazard ratio for risk of developing T2D was 1.7 (95% confidence interval [CI] 1.1-2.7) for the PPARG PP genotype, 1.5 (95% CI 1.0-2.2) for the CAPN10 SNP44 TT genotype, and 2.6 (95% CI 1.5-4.5) for the combination of PPARG and CAPN10 risk genotypes. In individuals with fasting plasma glucose > or = 5.6 mmol/l and body mass index > or = 30 kg/m(2), the hazard ratio increased to 21.2 (95% CI 8.7-51.4) for the combination of the PPARG PP and CAPN10 SNP43/44 GG/TT genotypes as compared to those with the low-risk genotypes with normal fasting plasma glucose and body mass index < 30 kg/m(2). CONCLUSION: We demonstrate in a large prospective study that variants in the PPARG and CAPN10 genes predict future T2D. Genetic testing might become a future approach to identify individuals at risk of developing T2D.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Adolescente , Adulto , Anciano , Glucemia , Índice de Masa Corporal , Femenino , Finlandia , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Estudios Prospectivos , Factores de Riesgo
10.
Diabetes ; 54(1): 166-74, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15616025

RESUMEN

Identification of individuals at high risk of developing type 2 diabetes is a prerequisite for prevention of the disease. We therefore studied risk factors predicting type 2 diabetes in the Botnia Study in Western Finland. A total of 2,115 nondiabetic individuals were prospectively followed with repeated oral glucose tolerance tests. After a median follow-up of 6 years, 127 (6%) subjects developed diabetes. A family history of diabetes (hazard ratio [HR] 2.2, P = 0.008), BMI (HR for comparison of values below or above the median 2.1, P < 0.001), waist-to-height index (2.3, P < 0.001), insulin resistance (2.1, P = 0.0004), and beta-cell function adjusted for insulin resistance (2.7, P < 0.0001) predicted diabetes. Marked deterioration in beta-cell function with modest changes in insulin sensitivity was observed during the transition to diabetes. The combination of FPG > or =5.6 mmol/l, BMI > or =30 kg/m(2), and family history of diabetes was a strong predictor of diabetes (3.7, P < 0.0001). Of note, using FPG > or =6.1 mmol/l or 2-h glucose > or =7.8 mmol/l did not significantly improve prediction of type 2 diabetes. In conclusion, a marked deterioration in beta-cell function precedes the onset of type 2 diabetes. These individuals can be identified early by knowledge of FPG, BMI, and family history of diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/sangre , Intolerancia a la Glucosa/fisiopatología , Insulina/metabolismo , Estado Prediabético/fisiopatología , Adulto , Glucemia/metabolismo , Índice de Masa Corporal , Colesterol/sangre , Femenino , Finlandia/epidemiología , Intolerancia a la Glucosa/sangre , Humanos , Secreción de Insulina , Lípidos/sangre , Estudios Longitudinales , Masculino , Anamnesis , Persona de Mediana Edad , Estado Prediabético/sangre , Factores de Riesgo , Fumar
11.
Diabetes Care ; 26(7): 1979-85, 2003 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12832299

RESUMEN

OBJECTIVE: To study cross-sectional associations of dietary fiber intake with insulin resistance, insulin secretion, and glucose tolerance in a population at high risk for type 2 diabetes. RESEARCH DESIGN AND METHODS: The subjects consisted of 248 male and 304 female adult nondiabetic relatives of patients with type 2 diabetes. Dietary intake was measured by means of two 3-day food records. Associations of total, water-insoluble, and water-soluble fiber with measures of glucose metabolism based on an oral glucose tolerance test, were analyzed by multiple linear regression analysis adjusting for sex, age, length of education, physical activity, BMI, waist-to-hip ratio, systolic blood pressure, and serum triglyceride and HDL cholesterol concentrations. The homeostasis model assessment insulin resistance index, the incremental 30-min serum insulin concentration divided by the incremental 30-min glucose concentration, and fasting and 2-h glucose concentrations were the outcome variables. RESULTS: The dietary intake of total as well as water-insoluble and water-soluble fiber was inversely associated with insulin resistance: -0.17 (0.07), P = 0.012; -0.15 (0.07), P = 0.024; and -0.14 (0.07), P = 0.049 [regression coefficients (SE)]. Fiber variables were unrelated to insulin secretion and plasma glucose concentrations. CONCLUSIONS: The results support evidence that a high intake of dietary fiber is associated with enhanced insulin sensitivity and therefore may have a role in the prevention of type 2 diabetes.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Fibras de la Dieta , Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Adulto , Glucemia/metabolismo , HDL-Colesterol/sangre , Registros de Dieta , Ingestión de Energía , Familia , Femenino , Prueba de Tolerancia a la Glucosa , Homeostasis , Humanos , Masculino , Análisis de Regresión , Triglicéridos/sangre
12.
Am J Clin Nutr ; 77(6): 1434-41, 2003 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12791620

RESUMEN

BACKGROUND: The role of antioxidants in the pathogenesis of type 2 diabetes is uncertain. OBJECTIVE: We evaluated cross-sectional relations of dietary intakes and plasma concentrations of antioxidants with glucose metabolism in a high-risk population. DESIGN: The subjects were 81 male and 101 female first- and second-degree, nondiabetic relatives of patients with type 2 diabetes. Antioxidant intake data were based on 3-d food records. Subjects taking supplements containing beta-carotene or alpha-tocopherol were excluded. Plasma antioxidant concentrations were measured by HPLC. By using multiple linear regression analysis and adjusting for demographic, anthropometric, and lifestyle covariates, we studied whether dietary and plasma alpha- and beta-carotene, lycopene, and alpha- and gamma-tocopherol were related to fasting and 2-h concentrations of glucose and nonesterified fatty acids during an oral-glucose-tolerance test, to the homeostasis model assessment index of insulin resistance, and to measures of beta cell function (incremental 30-min serum insulin concentration during an oral-glucose-tolerance test and first-phase insulin secretion during an intravenous-glucose-tolerance test). RESULTS: In men, dietary carotenoids were inversely associated with fasting plasma glucose concentrations (P < 0.05), plasma beta-carotene concentrations were inversely associated with insulin resistance (P = 0.003), and dietary lycopene was directly related to baseline serum concentrations of nonesterified fatty acids (P = 0.034). In women, dietary alpha-tocopherol and plasma beta-carotene concentrations were inversely and directly associated, respectively, with fasting plasma glucose concentrations (P < 0.05). In both sexes, cholesterol-adjusted alpha-tocopherol concentrations were directly associated with 2-h plasma glucose concentrations (P < 0.05). CONCLUSION: The data suggest an advantageous association of carotenoids, which are markers of fruit and vegetable intake, with glucose metabolism in men at high risk of type 2 diabetes.


Asunto(s)
Carotenoides/administración & dosificación , Carotenoides/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/etiología , Glucosa/metabolismo , Tocoferoles/administración & dosificación , Tocoferoles/sangre , Adulto , Estudios Transversales , Dieta , Ayuno/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Concentración Osmolar , Estudios Prospectivos , Factores de Riesgo , Caracteres Sexuales
13.
Diabetes Care ; 25(12): 2141-6, 2002 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-12453951

RESUMEN

OBJECTIVE: The purpose of this study was to evaluate the metabolic effectiveness, safety, and tolerability of nateglinide in subjects with impaired glucose tolerance (IGT) and to identify a dose appropriate for use in a diabetes prevention study. RESEARCH DESIGN AND METHODS: This multicenter, double-blind, randomized, parallel-group, fixed-dose study of 8 weeks' duration was performed in a total of 288 subjects with IGT using a 2:2:2:1 randomization. Subjects received nateglinide (30, 60, and 120 mg) or placebo before each main meal. Metabolic effectiveness was assessed during a standardized meal challenge performed before and after the 8-week treatment. All adverse events (AEs) were recorded, and confirmed hypoglycemia was defined as symptoms accompanied by a self-monitoring of blood glucose measurement < or =3.3 mmol/l (plasma glucose < or =3.7 mmol/l). RESULTS: Nateglinide elicited a dose-related increase of insulin and a decrease of glucose during standardized meal challenges, with the predominant effect on early insulin release, leading to a substantial reduction in peak plasma glucose levels. Nateglinide was well tolerated, and symptoms of hypoglycemia were the only treatment-emergent AEs. Confirmed hypoglycemia occurred in 28 subjects receiving nateglinide (30 mg, 0 [0%]; 60 mg, 5 [6.6%]; 120 mg, 23 [26.7%]) and in 1 (2.3%) subject receiving placebo. CONCLUSIONS: Nateglinide was safe and effective in reducing postprandial hyperglycemia in subjects with IGT. Preprandial doses of 30 or 60 mg nateglinide would be appropriate to use for longer-term studies to determine whether a rapid-onset, rapidly reversible, insulinotropic agent can delay or prevent the development of type 2 diabetes.


Asunto(s)
Glucemia/metabolismo , Ciclohexanos/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Fenilalanina/uso terapéutico , Estado Prediabético/sangre , Estado Prediabético/tratamiento farmacológico , Adulto , Anciano , Glucemia/efectos de los fármacos , Índice de Masa Corporal , Método Doble Ciego , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Secreción de Insulina , Masculino , Persona de Mediana Edad , Nateglinida , Fenilalanina/análogos & derivados , Periodo Posprandial
14.
J Clin Endocrinol Metab ; 87(9): 4171-6, 2002 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-12213867

RESUMEN

Nateglinide is a fast-acting insulin secretion agent that specifically targets postprandial hyperglycemia in patients with type 2 diabetes. The recent reduction in the diagnostic criteria for diabetes and improved understanding of the importance of early insulin secretion served as the rationale for this multicenter, double-blind, randomized, parallel-group, 24-wk study performed in 675 patients with type 2 diabetes but only moderately elevated fasting plasma glucose (FPG) (FPG = 7.0-8.3 mmol/liter) to assess the efficacy and safety of three fixed doses of nateglinide (30, 60, or 120 mg, with meals). A substudy of the effects on early insulin release and prandial glucose excursions following a standardized breakfast was performed in 127 subjects. Nateglinide was well tolerated and elicited a dose-dependent reduction of placebo-adjusted hemoglobin A(1c) (Delta = -0.26 to -0.39%) and FPG (Delta = -0.51 to -0.73 mmol/liter) accompanied by a dose-related increase in suspected hypoglycemic episodes. However, confirmed hypoglycemia occurred in only 5.3% of patients treated with the highest dose, compared with 1.2% in placebo-treated patients (P < 0.05). Nateglinide increased early insulin release and reduced prandial glucose excursions (P < 0.05 vs. placebo). In sum, nateglinide is a safe and effective therapeutic option for treatment of patients with mild to moderate fasting hyperglycemia.


Asunto(s)
Glucemia/metabolismo , Ciclohexanos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hiperglucemia/etiología , Hipoglucemiantes/uso terapéutico , Fenilalanina/análogos & derivados , Fenilalanina/uso terapéutico , Adulto , Glucemia/efectos de los fármacos , Ciclohexanos/efectos adversos , Diabetes Mellitus Tipo 2/sangre , Método Doble Ciego , Ayuno , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hiperglucemia/tratamiento farmacológico , Hipoglucemia/epidemiología , Hipoglucemiantes/efectos adversos , Incidencia , Insulina/sangre , Insulina/metabolismo , Secreción de Insulina , Masculino , Nateglinida , Fenilalanina/efectos adversos , Grupos Raciales , Resultado del Tratamiento
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