The influence of high-density lipoprotein (HDL) and HDL subfractions on insulin secretion and cholesterol efflux in pancreatic derived ß-cells.

BACKGROUND: High-density lipoprotein (HDL) is considered a complex plasma-circulating particle with subfractions that vary in function, size, and chemical composition. We sought to test the effects of HDL, and HDL subfractions on insulin secretion and cholesterol efflux in the ß-cell line MIN-6. METHODS: We used total HDL and HDL subfractions 2a, 2b, 3a, 3b, and 3c, isolated from human plasma, to test insulin secretion under different glucose concentrations as well as insulin content and cholesterol efflux in the insulinoma MIN-6 cell line. RESULTS: Incubation of MIN-6 cells with low glucose and total HDL increased insulin release two-fold. Meanwhile, when high glucose and HDL were used, insulin release increased more than five times. HDL subfractions 2a, 2b, 3a, 3b, and 3c elicited higher insulin secretion and cholesterol efflux than their respective controls, at both low and high glucose concentrations. The insulin content of the MIN-6 cells incubated with low glucose and any of the five HDL subclasses had a modest reduction compared with their controls. However, there were no statistically significant differences between each HDL subfraction on their capacity of eliciting insulin secretion, insulin content, or cholesterol efflux. CONCLUSIONS: HDL can trigger insulin secretion under low, normal, and high glucose conditions. We found that all HDL subfractions exhibit very similar capacity to increase insulin secretion and cholesterol efflux. This is the first report demonstrating that HDL subfractions act both as insulin secretagogues (under low glucose) and insulin secretion enhancers (under high glucose) in the MIN-6 cell line.

The -514C>T polymorphism in the LIPC gene modifies type 2 diabetes risk through modulation of HDL-cholesterol levels in Mexicans.

PURPOSE: Both type 2 diabetes (T2D) and low levels of high-density lipoprotein cholesterol (HDL-C) are very prevalent conditions among Mexicans. Genetic variants in the LIPC gene have been associated with both conditions. This study aimed to evaluate the association of the -514C < T (rs1800588) LIPC gene polymorphism with different metabolic traits, particularly the effects of this polymorphism on HDL-C plasma levels and T2D risk. METHODS: Mediation analysis was used to assess the direct and indirect effects of the -514C>T LIPC gene variant on HDL-C levels, T2D risk, and body mass index (BMI), in 2105 Mexican mestizo participants. We also assessed the functional effect of the -514C>T LIPC variant on the promoter activity of a reporter gene in the HepG2 cell line. RESULTS: Direct effects show that the -514C>T LIPC polymorphism is significantly associated with increased HDL-C plasma levels (ß = 0.03; p < 0.001). The -514C>T variant resulted in an indirect protective effect on T2D risk through increasing HDL-C levels (ß = - 0.03; p < 0.001). Marginal direct association between -514C>T and T2D was found (ß = 0.08; p = 0.06). Variables directly influencing T2D status were European ethnicity (ß = - 7.20; p < 0.001), age (ß = 0.04; p < 0.001), gender (ß = - 0.15; p = 0.017) and HDL-C (ß = - 1.07; p < 0.001). In addition, we found that the -514C>T variant decreases the activity of LIPC promoter by 90% (p < 0.001). CONCLUSIONS: The -514C>T polymorphism was not directly associated with T2D risk. HDL-C acts as a mediator between -514C>T LIPC gene variant and T2D risk in the Mexican population.

R230C but not - 565C/T variant of the ABCA1 gene is associated with type 2 diabetes in Mexicans through an effect on lowering HDL-cholesterol levels.

PURPOSE: Type 2 diabetes (T2D) and low serum concentration of high-density lipoprotein cholesterol (HDL-c) are common coexisting metabolic disorders. ABCA1 variants have been shown to be associated to these conditions. We sought to test the combined effect of two ABCA1 gene common variants, rs2422493 (- 565C > T) and rs9282541 (R230C) on HDL-c levels and T2D risk. METHODS: Path analysis was conducted in 3,303 Mexican-mestizos to assess the specific contributions of rs2422493 and rs9282541 ABCA1 variants, insulin resistance, waist-to-height ratio (WHtR), and age on HDL-c levels and T2D risk. Participants were classified into four groups according to their ABCA1 variants carrier status: (i) the reference group carried wild type alleles for both ABCA1 variants (-/-), (ii) +/- were carriers of rs2422493 but non-carriers of rs9282541, (iii) -/+ for carriers of rs9282541 but not carriers of rs2422493 and (iv) carriers of minor alleles for both SNPs (+/+). Principal components from two previous genome-wide association studies were used to control for ethnicity. RESULTS: We identified significant indirect effects on T2D risk mediated by HDL-c in groups -/+ and +/+ (ß = 0.04; p = 0.03 and ß = 0.06; p < 0.01, respectively) in comparison to the -/- reference group. Low concentrations of HDL-c were directly and significantly associated with increased T2D risk (ß = -0.70; p < 0.01). WHtR, male gender, age, and insulin resistance were also associated with T2D risk (p < 0.05). There was no significant direct effect for any of the ABCA1 groups on T2D risk: p = 0.99, p = 0.58, and p = 0.91 for groups +/-, -/+, and +/+ respectively. CONCLUSIONS: The ABCA1 rs9282541 (R230C) allele is associated with T2D in Mexicans through its effect on lowering HDL-c levels. This is the first report demonstrating that HDL-c levels act as an intermediate factor between an ABCA1 variant and T2D.

Hospital arrival time and functional outcome after acute ischaemic stroke: results from the PREMIER study.

INTRODUCTION: Information regarding hospital arrival times after acute ischaemic stroke (AIS) has mainly been gathered from countries with specialised stroke units. Little data from emerging nations is available. We aim to identify factors associated with achieving hospital arrival times of less than 1, 3, and 6 hours, and analyse how arrival times are related to functional outcomes after AIS. METHODS: We analysed data from patients with AIS included in the PREMIER study (Primer Registro Mexicano de Isquemia Cerebral) which defined time from symptom onset to hospital arrival. The functional prognosis at 30 days and at 3, 6, and 12 months was evaluated using the modified Rankin Scale. RESULTS: Among 1096 patients with AIS, 61 (6%) arrived in <1 hour, 250 (23%) in <3 hours, and 464 (42%) in <6 hours. The factors associated with very early (<1 hour) arrival were family history of ischemic heart disease and personal history of migraines; in <3 hours: age 40-69 years, family history of hypertension, personal history of dyslipidaemia and ischaemic heart disease, and care in a private hospital; in <6 hours: migraine, previous stroke, ischaemic heart disease, care in a private hospital, and family history of hypertension. Delayed hospital arrival was associated with lacunar stroke and alcoholism. Only 2.4% of patients underwent thrombolysis. Regardless of whether or not thrombolysis was performed, arrival time in <3 hours was associated with lower mortality at 3 and 6 months, and with fewer in-hospital complications. CONCLUSIONS: A high percentage of patients had short hospital arrival times; however, less than 3% underwent thrombolysis. Although many factors were associated with early hospital arrival, it is a priority to identify in-hospital barriers to performing thrombolysis.

Tiempo de llegada hospitalaria y pronóstico funcional después de un infarto cerebral: resultados del estudio PREMIER / Hospital arrival time and functional outcome after acute ischaemic stroke: Results from the PREMIER study

Introducción: La información sobre el tiempo de llegada hospitalaria después de un infarto cerebral (IC) se ha originado en países con unidades especializadas en ictus. Existe poca información en naciones emergentes. Nos propusimos identificar los factores que influyen en el tiempo de llegada hospitalaria a 1, 3 y 6 h y su relación con el pronóstico funcional después del ictus. Métodos: Se analizó la información de pacientes con IC incluidos en el estudio Primer Registro Mexicano de Isquemia Cerebral (PREMIER) que tuvieran tiempo definido desde el inicio de los síntomas hasta la llegada hospitalaria. El desenlace funcional se evaluó mediante la escala modificada de Rankin a los 30 días, 3, 6 y 12 meses. Resultados: De 1.096 pacientes con IC, 61 (6%) llegaron en < 1 h, 250 (23%) en < 3 h y 464 (42%) en < 6 h. Favorecieron la llegada temprana en < 1 h: el antecedente familiar de cardiopatía isquémica y ser migrañoso; en < 3 h: edad 40-69 años, antecedente familiar de hipertensión, antecedente personal de dislipidemia y cardiopatía isquémica, así como la atención en hospital privado; en < 6 h: antecedente familiar de hipertensión, ser migrañoso, ictus previo, cardiopatía isquémica y atención en hospital privado. La llegada hospitalaria tardía se asoció a ictus lacunar y alcoholismo. Solo el 2,4% recibió trombólisis. Independientemente de la trombólisis, la llegada en < 3 h se asoció a menor mortalidad a los 3 y 6 meses, además de menos complicaciones intrahospitalarias. Conclusiones: Una proporción importante de pacientes tuvo un tiempo de llegada hospitalaria temprana; sin embargo, menos del 3% recibió trombólisis. Aunque muchos factores se asociaron a la llegada temprana, es prioritario identificar las barreras intrahospitalarias que obstaculizan la trombólisis

Introduction: Information regarding hospital arrival times after acute ischaemic stroke (AIS) has mainly been gathered from countries with specialised stroke units. Little data from emerging nations is available. We aim to identify factors associated with achieving hospital arrival times of less than 1, 3, and 6 hours, and analyse how arrival times are related to functional outcomes after AIS. Methods: We analysed data from patients with AIS included in the PREMIER study (Primer Registro Mexicano de Isquemia Cerebral) which defined time from symptom onset to hospital arrival. The functional prognosis at 30 days and at 3, 6, and 12 months was evaluated using the modified Rankin Scale. Results: Among 1096 patients with AIS, 61 (6%) arrived in <1 hour, 250 (23%) in <3 hours, and 464 (42%) in <6 hours. The factors associated with very early (<1 hour) arrival were family history of ischemic heart disease and personal history of migraines; in <3 hours: age 40-69 years, family history of hypertension, personal history of dyslipidaemia and ischaemic heart disease, and care in a private hospital; in <6 hours: migraine, previous stroke, ischaemic heart disease, care in a private hospital, and family history of hypertension. Delayed hospital arrival was associated with lacunar stroke and alcoholism. Only 2.4% of patients underwent thrombolysis. Regardless of whether or not thrombolysis was performed, arrival time in <3 hours was associated with lower mortality at 3 and 6 months, and with fewer in-hospital complications. Conclusions: A high percentage of patients had short hospital arrival times; however, less than 3% underwent thrombolysis. Although many factors were associated with early hospital arrival, it is a priority to identify in-hospital barriers to performing thrombolysis