RESUMO
AIMS: Heterozygous activating mutations in KCNJ11, which encodes the Kir6.2 subunit of the pancreatic ATP-sensitive potassium (K(ATP)) channel, cause both permanent and transient neonatal diabetes. Identification of KCNJ11 mutations has important therapeutic implications, as many patients can replace insulin injections with sulphonylurea tablets. The aim was to determine if a KCNJ11 mutation was responsible for a dominantly inherited form of diabetes mellitus, showing variability in age at diagnosis, in an Italian family. METHODS: We sequenced KCNJ11 in members of a three-generation family with variable phenotypes of dominantly inherited diabetes mellitus. One had transient early-onset diabetes, one had impaired glucose tolerance during the second pregnancy, and two had young-onset diabetes. None of the subjects showed permanent neonatal diabetes or neurological symptoms. RESULTS: A novel heterozygous mutation (c. 679C-->G and c. 680A-->T) was identified, resulting in a GAG-->CTG (E227L) substitution in KCNJ11. Functional studies of recombinant heterozygous K(ATP) channels revealed a small reduction in channel inhibition by ATP (IC(50) of 15 micromol/l and 38 micromol/l for wild-type and heterozygous channels, respectively) and an increase in the resting K(ATP) current. This would be expected to impair insulin secretion. The results are in agreement with the mild phenotype of the patients. CONCLUSIONS: Our results broaden the spectrum of diabetes phenotypes resulting from KCNJ11 mutations. They indicate testing for KCNJ11 mutations should be considered not only for neonatal diabetes but also for other forms of dominantly inherited diabetes with later onset, especially where these are associated with a low body mass index and low birth weight.
Assuntos
Diabetes Mellitus/genética , Mutação/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Adulto , Feminino , Heterozigoto , Humanos , Masculino , Linhagem , Fenótipo , GravidezRESUMO
BACKGROUND: Rapid weight loss after bariatric surgery is associated with a high prevalence of gallstone formation. In laparoscopic Roux-en-Y gastric bypass (RYGBP), the bypassed segment is not readily available for endoscopic or radiographic examination. We propose a laparoscopic Janeway gastrostomy for secondary access to excluded structures in bariatric centers with no mandatory technical equipment in endoscopic retrograde cholangiopancreatography (ERCP), double-balloon ERCP or spiral enteroscopy. METHOD: This was a single-institution retrospective review of a prospectively collected database of patients with a history of laparoscopic RYGBP who underwent laparoscopic Janeway gastrostomy for duodenal and biliary access. The operative indications, technical aspects, endoscopic findings, outcomes, and complications were investigated. RESULTS: Five patients with a history of RYGBP underwent laparoscopic Janeway gastrostomy for exploration of the bypassed segment. All of them had biliary pathology, and all underwent successful ERCP and papillotomy. The gastrostomies were closed secondarily. The mean duration of hospitalization was 12 days. No complications developed. All procedures were performed laparoscopically. CONCLUSION: If access to excluded structures and simultaneous ERCP was not possible, temporary laparoscopic Janeway gastrostomy could be the last option alternative for a staged ERCP to gain access to the bypassed structures. It is a feasible and safe solution for the exploration and treatment of patients with a history of RYGBP in bariatric centers that have no endoscopists with expertise in ERCP.
Assuntos
Colangiopancreatografia Retrógrada Endoscópica/métodos , Cálculos Biliares/cirurgia , Derivação Gástrica , Gastrostomia/métodos , Laparoscopia , Complicações Pós-Operatórias/cirurgia , Adulto , Feminino , Seguimentos , Cálculos Biliares/diagnóstico , Cálculos Biliares/etiologia , Derivação Gástrica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/diagnóstico , Estudos Retrospectivos , Esfinterotomia Endoscópica/métodosRESUMO
So far, Streptococcus devriesei, which belongs to the mutans streptococci group, has been incriminated in the formation of caries in Equidae. We report the first human infection due to this species in a 54-year-old man with gangrenous cholecystitis. The patient was treated successfully by cholecystectomy and ceftriaxone.
RESUMO
Laparoscopic Roux-en-Y gastric bypass is one of the most commonly performed bariatric procedures and most patients are women of reproductive age. Consequently, general surgeons and obstetricians need to be aware that these patients are at risk of bariatric specific surgical complications during their pregnancy. We report a case involving a 32-year-old woman who had undergone Roux-en-Y gastric bypass surgery 2 years previously. She presented at 25 weeks of gestation with a closed loop obstruction due to a retrograde jejunojejunal intussusception that was initially misdiagnosed as acute pancreatitis.
Assuntos
Anastomose em-Y de Roux/efeitos adversos , Derivação Gástrica/efeitos adversos , Obstrução Intestinal , Intussuscepção , Complicações na Gravidez , Adulto , Proteína C-Reativa/análise , Feminino , Humanos , Laparoscopia , Lipase/sangue , Pessoa de Meia-Idade , GravidezRESUMO
BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) remains one of the most performed bariatric procedures worldwide, but a few long-term studies have been reported often with limited data at time of longest follow-up. We review our 18-year LAGB experience with special regard to weight loss failure and long-term complications leading to band removal. METHODS: We performed 897 LAGB procedures from April 1996 to December 2007: 376 using the perigastric dissection and 521 using the pars flaccida dissection. We performed a retrospective analysis of the data of this consecutive series. Failure was defined as band removal with or without conversion to another procedure or excess weight loss (EWL%) <25 %. RESULTS: There were 120 men and 770 women. Mean age was 39.5 years, and mean BMI was 45.6 kg/m2. Mean follow-up was 14.6 years (range 101-228 months) with 90 % follow-up beyond 10 years. Ten (1.1 %) had early complications and 504 (56 %) late complications. Overall, 374 (41.6 %) bands were explanted for complications, weight regain, or intolerance. Mean 15-year EWL% in patients with band in place was 41.73 %. Over time, band failure rate increases from 18.4 % at 2 years to 43 % at 10 years and more than 70 % beyond 15 years. CONCLUSIONS: Despite good initial results, late complications, weight regain, and intolerance lead to band removal in nearly half of the patients over time. However, given that there is no good information on alternative procedures in the long term and considering its reversibility and safety still has a place in the treatment of morbid obesity for informed and motivated patients.
Assuntos
Gastroplastia , Obesidade Mórbida/cirurgia , Adulto , Feminino , Seguimentos , Gastroplastia/métodos , Gastroplastia/reabilitação , Hospitais Universitários , Humanos , Laparoscopia/métodos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/reabilitação , Reoperação , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Redução de PesoRESUMO
The harderian gland (HG) is an orbital gland of the vast majority of land vertebrates. In the Syrian hamster these glands display a marked sexual dimorphism. Here we present data on a male specific clone named MHG30. The MHG30 cDNA (1470 bp) has significant sequence homologies with human #15µ10#Δ6-desaturase enzymes. The expression of MHG30 has been found in male HG and in the liver of both sexes, no other tissue showing the presence of MHG30 mRNA. Castration brings the MHG30 levels below detectable level in about 7 days. In in vitro cultures of male hamster HG cells, androgens (A) determine an enhancement of MHG30 expression in a time-dependent manner. Conversely, a continuous decrement has been observed in control cells and in cells treated with A plus flutamide (F) or with A and cycloheximide (Cy). Incubation of cells in cultures supplemented with desamethason (Dex) or thyroid hormone (T3) also increases MHG30 expression while 17ß-estradiol prevents the stimulatory effect exerted by A, Dex and T3. Findings strongly suggest that the MHG30 gene could be involved in supporting the sexual dimorphism and its expression is likely triggered by a series of hormonal interactions.
Assuntos
Ácidos Graxos Dessaturases/genética , Regulação Enzimológica da Expressão Gênica/fisiologia , Glândula de Harder/enzimologia , Hormônios/fisiologia , Animais , Sequência de Bases , Castração , Cricetinae , DNA Complementar , Masculino , Mesocricetus , Dados de Sequência MolecularRESUMO
The aim of this study was to evaluate the role of diabetes and minor abnormalities of glucose homeostasis, such as impaired glucose tolerance, as determinants of cardiac function and structure in a working population. We studied a population-based sample of 64 telephone company employees (both sexes, mean age 58 years): 25 with normoglycemia, 15 with impaired glucose tolerance, and 24 with non-insulin-dependent diabetes mellitus (NIDDM) diagnosed by oral glucose tolerance test according to the recommendations of the World Health Organization. Subjects with myocardial ischemia were excluded. Left ventricular end-systolic dimension, indexed to body surface area, was greater in those with NIDDM (p < 0.05) and in those with impaired glucose tolerance (p < 0.05) with respect to normoglycemic persons. The ratio of the peak early diastolic velocity wave to the late diastolic wave was lower in those with NIDDM (p < 0.05) and in those with impaired glucose tolerance (p < 0.05) than in participants with normoglycemia. Body mass index and blood pressure were similar in the 3 groups. These results clearly indicate that early abnormalities of cardiac structure and function are observed not only in patients with NIDDM, but also in those with impaired glucose tolerance, independent of the confounding role of myocardial ischemia, body weight, and blood pressure.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Intolerância à Glucose/fisiopatologia , Coração/fisiopatologia , Adulto , Arritmias Cardíacas/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Ecocardiografia Doppler , Eletrocardiografia , Feminino , Intolerância à Glucose/complicações , Intolerância à Glucose/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The relation between 24-h ambulatory blood pressure monitoring and echocardiographic left ventricular (LV) anatomy and function was examined in 30 young, normotensive offspring (16 men, 14 women) of hypertensive, parents and in 20 offspring (12 men, 8 women) of normotensive parents, comparable for age, clinical blood pressure, and gender. Offspring of hypertensive subjects exhibited higher body mass index (P < .01), relative wall thickness, and LV mass/height (both P < .001). No significant difference was found in LV chamber dimensions and in either systolic or diastolic function. The 24-h systolic and diastolic blood pressures were higher in offspring of hypertensive subjects than in controls (P < .001 and P < .0001, respectively), as was the coefficient of variation of 24 h systolic blood pressure (P < .01). In pooled groups, LV mass was positively related to daytime systolic blood pressure (r = 0.48), daytime diastolic blood pressure (r = 0.47) (both P < .001), and the coefficient of variation of 24 h diastolic blood pressure (r = 0.37, P < .01). In a multiple regression model, including as variables, body mass index, daytime systolic and diastolic blood pressures, male gender, and family history of hypertension were the major independent predictors of LV mass (both P < .0001), with an additional contribution of the coefficient of variation of 24 h diastolic blood pressure (P < .05). We conclude that male gender and a family history of hypertension are stronger determinants of early changes in cardiac structure than hemodynamic load in a group of young, normotensive adults.
Assuntos
Determinação da Pressão Arterial/métodos , Ventrículos do Coração/anatomia & histologia , Hipertensão/genética , Hipertensão/fisiopatologia , Função Ventricular , Adolescente , Adulto , Assistência Ambulatorial , Monitores de Pressão Arterial , Índice de Massa Corporal , Ritmo Circadiano/fisiologia , Ecocardiografia Doppler , Feminino , Hemodinâmica , Humanos , Masculino , Análise de Regressão , Caracteres SexuaisRESUMO
Antihypertensive efficacy, effects on left ventricular mass index (LVMI) and tolerability of telmisartan, an angiotensin II receptor blocker, were compared with those of hydrochlorothiazide (HCTZ). Adult patients with mild-to-moderate hypertension and an optimal acoustic window by two-dimensional echocardiography were randomised at baseline to 12 months' double-blind, once-daily treatment with telmisartan 80 mg or HCTZ 25 mg. Two-dimensional echocardiography and freehand precordial three-dimensional echocardiography and 24-h ambulatory blood pressure monitoring were performed at baseline and after treatment. Of the 41 telmisartan group patients and 28 HCTZ group patients, 40 and 25, respectively, completed the study. Following treatment, 24-h mean SBP (telmisartan 157 +/- 11 vs 133 +/- 7 mmHg, P<0.001; HCTZ 154 +/- 10 vs 144 +/- 11 mmHg, P<0.003) and DBP (telmisartan 96 +/- 6 vs 83 +/- 5 mmHg, P<0.001; HCTZ 95 +/- 7 vs 87 +/- 8 mmHg, P<0.003) were significantly reduced. Telmisartan produced significantly greater 24-h mean SBP and DBP reductions than HCTZ (P<0.001). LVMI was significantly reduced by telmisartan (141 +/- 16 vs 125 +/- 19 g/m2, P<0.001), but not by HCTZ (139 +/- 20 vs 135 +/- 22 g/m(2)). Incidences of adverse events in both the treatment groups were low; two cases of hypokalaemia occurred with HCTZ. In conclusion, telmisartan 80 mg was well tolerated and significantly reduced SBP, DBP and LVMI after 12 months' treatment compared with HCTZ.
Assuntos
Anti-Hipertensivos/uso terapêutico , Benzimidazóis/uso terapêutico , Benzoatos/uso terapêutico , Hidroclorotiazida/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Adulto , Idoso , Antagonistas de Receptores de Angiotensina , Pressão Sanguínea/efeitos dos fármacos , Monitorização Ambulatorial da Pressão Arterial , Método Duplo-Cego , Ecocardiografia Tridimensional , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Telmisartan , Resultado do TratamentoRESUMO
The aim of the present study was to evaluate the effect of dihydropyridine calcium antagonist isradipine on left ventricular (LV) structure and function in patients with essential hypertension. Cuff blood pressure and Doppler echocardiographic variables were assessed in 26 patients with mild to moderate hypertension (diastolic blood pressure range 95-110 mmHg) before and after 12 weeks of therapy with either isradipine 5 mg daily or enalapril 20 mg daily. The study was of double-blind, parallel design, with a placebo run-in period of 15 days. Three subjects withdrew from isradipine treatment because of flushing and 2 from enalapril treatment due to cough before completing the study. Both drugs significantly reduced cuff systolic and diastolic blood pressure (p < 0.001) without affecting heart rate. By virtue of the decrease in both septal wall (p < 0.01) and posterior wall thicknesses (p < 0.05), isradipine treatment produced a significant reduction in LV mass adjusted for height (p < 0.001) in comparison with placebo; also LV end-systolic dimension showed a slight decrease (p < 0.05). Enalapril induced a similar reduction in LV end-systolic dimension (p < 0.05) but the changes of wall thickness and LV mass did not reach statistical significance. In conclusion, our results indicate that isradipine treatment improves LV systolic function and causes a significant reduction in LV mass. This reduction is observed early in the course of antihypertensive treatment and is effective in both patients with and without LV hypertrophy.
Assuntos
Anti-Hipertensivos/uso terapêutico , Enalapril/uso terapêutico , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Isradipino/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Ecocardiografia Doppler , Feminino , Humanos , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/patologia , Masculino , Pessoa de Meia-Idade , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
The effects of 60 mg/day nicardipine hydrochloride were evaluated in a 4-week single-blind study on 12 patients with chronic stable effort angina. All patients completed the treatment with few reports of adverse effects. Nicardipine hydrochloride was effective in reducing the incidence of anginal attacks and consumption of glyceryl trinitrate. Treadmill exercise time, angina onset time and the time to 1 mm ST-segment depression were increased. The extent of ST-segment depression was reduced at maximum comparable exercise, with a reduced rate-pressure product and, at maximum exercise, with an increased rate-pressure product. Myocardial stress 201Tl scintillography was carried out in eight of the patients and showed improved washout in antero-septal, infero-apical and postero-lateral segments. Echocardiographic measures of left ventricular function were enhanced because of reduction of afterload. Systemic vascular resistance and end-systolic stress were also decreased and a significant correlation was found between the increase in ejection fraction and reduction of systolic blood pressure. It is concluded that nicardipine hydrochloride is effective in the control of stable effort angina by reducing myocardial oxygen consumption and enhancing coronary blood flow thereby improving left ventricular function.
Assuntos
Angina Pectoris/tratamento farmacológico , Nicardipino/uso terapêutico , Angina Pectoris/fisiopatologia , Doença Crônica , Ecocardiografia , Teste de Esforço , Feminino , Coração/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Cintilografia , Radioisótopos de TálioRESUMO
The antihypertensive and haemodynamic efficacies of ketanserin and ketanserin plus enalapril were compared. The monotherapy phase of the study involved the oral administration of 40 mg ketanserin twice daily or 20 mg enalapril once daily for 12 weeks to 25 hypertensive patients. Systolic and diastolic blood pressures were significantly reduced by both drugs. Left ventricular function both at rest and during effort improved significantly with either drug. This was due to a reduction of end-systolic volume; end-diastolic volume decreased only with the use of enalapril. Combination therapy, involving 16 patients and both drugs given at the original dosage schedule for 12 weeks, resulted in further reductions in systolic and diastolic blood pressures, and an improvement in left ventricular function; indices of diastolic function were not modified. In conclusion, ketanserin and enalapril showed comparable antihypertensive and haemodynamic activities. A combination of ketanserin and enalapril increased the favourable characteristics of both drugs.
Assuntos
Enalapril/administração & dosagem , Hipertensão/tratamento farmacológico , Ketanserina/administração & dosagem , Idoso , Pressão Sanguínea , Método Duplo-Cego , Esquema de Medicação , Quimioterapia Combinada , Feminino , Humanos , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Volume Sistólico , Função Ventricular EsquerdaRESUMO
A total of 20 untreated hypertensive patients were divided into two equal groups matched for sex, age and blood pressure but with [mean diastolic wall thickness (MDWT) greater than 1.2 cm] or without (MDWT greater than 1.2 cm) left ventricular hypertrophy (LVH). All patients underwent pulsed doppler echocardiography and 99Tc radionuclide ventriculography at rest to assess diastolic and systolic abnormalities. In hypertensives with LVH the interventricular wall thickness, posterior wall thickness and relative diastolic wall thickness were significantly (P less than 0.01) higher and peak filling rate was significantly (P less than 0.01) lower than in hypertensives without LVH. The indices of systolic function, however, were not significantly different in the two patient groups. In hypertensives without LVH peak filling rate directly correlated with heart rate, whereas in those with LVH peak filling rate directly correlated with heart rate and the ratio of peak velocity of early left ventricular filling : peak velocity of late left ventricular filling due to atrial contraction. It is concluded that diastolic parameters may be useful tools for assessing myocardial compliance and may be effective markers of diastolic dysfunction.
Assuntos
Cardiomegalia/fisiopatologia , Hipertensão/fisiopatologia , Adulto , Pressão Sanguínea/fisiologia , Cardiomegalia/complicações , Diástole , Ecocardiografia Doppler/métodos , Feminino , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Ventriculografia com Radionuclídeos/métodos , Função Ventricular Esquerda/fisiologiaRESUMO
In order to clarify the role of age and hypertension in determining arrhythmias, we evaluated the average heart rate, and the number of supraventricular and ventricular premature beats and their severity (Lown grade) by 24-h Holter electrocardiography of 336 patients. We excluded 54 patients with prolonged runs of atrial fibrillation or supraventricular tachycardia because these arrhythmias reduce the possibility of determining the number of premature beats. Analysis of variance, carried out after dividing the patients into four different groups according to age and blood pressure (excluding patients aged 60-65 years with diastolic blood pressure of 91-94 mmHg) showed that the hypertensives had a higher average heart rate (P less than 0.01) and more supraventricular (P less than 0.05) and premature ventricular (P less than 0.01) beats than the normotensives; no difference was found among groups of different ages. The severity of premature ventricular beats was higher in hypertensives than in normotensives, and also higher in elderly than in 'young' patients (P less than 0.01). In the evaluation of all 336 patients we found correlations between age and severity of premature ventricular beats in both normotensives (P less than 0.05) and hypertensives (P less than 0.001). Multilinear regression showed that mean blood pressure was independently related to the average heart rate, and supraventricular and premature ventricular beats and their severity, while age was correlated independently only with the severity of premature ventricular beats (P less than 0.001). We conclude that hypertension induces arrhythmias, and that age increases their severity.
Assuntos
Arritmias Cardíacas/fisiopatologia , Eletrocardiografia , Hipertensão/fisiopatologia , Fatores Etários , Idoso , Análise de Variância , Arritmias Cardíacas/etiologia , Pressão Sanguínea , Feminino , Frequência Cardíaca , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Análise de Regressão , Índice de Gravidade de DoençaRESUMO
Our aim was to assess echocardiographic parameters and the effort blood pressure of 50 children of hypertensives with respect to 50 children of normotensives. Systolic and diastolic blood pressures at rest were comparable between the two groups. Left ventricular mass index (LVMI), interventricular septum and posterior wall thicknesses were higher in children of hypertensives (P less than 0.01). Systolic blood pressure was higher in children of hypertensives at maximal effort until 5 min of recovery (P less than 0.01). Similarly, diastolic blood pressure was higher at 1 and 2 min of recovery (P less than 0.01). Direct correlations of mean diastolic wall thickness (r = 0.39, P less than 0.01) and LVMI (r = 0.33, P less than 0.05) with percentage effort systolic blood pressure increases were found in children of hypertensives but not in children of normotensives. In conclusion, we confirmed early cardiac alterations and a tendency for effort hypertension in children of hypertensives. The relationship between these data could be explained either by effort systolic overload or by a common response to an increased adrenergic stimulus.
Assuntos
Hipertensão/genética , Adulto , Pressão Sanguínea , Ecocardiografia , Frequência Cardíaca , Humanos , Hipertensão/patologia , Miocárdio/patologiaAssuntos
Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Adulto , Diástole/fisiologia , Família , Feminino , Hemodinâmica/fisiologia , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Ultrassonografia , Função Ventricular Esquerda/fisiologiaAssuntos
Cardiomegalia/etiologia , Hidrogênio/metabolismo , Hipertensão/metabolismo , Sódio/metabolismo , Adulto , Proteínas de Transporte/metabolismo , Feminino , Humanos , Hipertensão/complicações , Troca Iônica , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Trocadores de Sódio-HidrogênioRESUMO
AIMS/HYPOTHESIS: Heterozygous activating mutations in the pancreatic ATP-sensitive K+ channel cause permanent neonatal diabetes mellitus (PNDM). This results from a decrease in the ability of ATP to close the channel, which thereby suppresses insulin secretion. PNDM mutations that cause a severe reduction in ATP inhibition may produce additional symptoms such as developmental delay and epilepsy. We identified a heterozygous mutation (L164P) in the pore-forming (Kir6.2) subunit of the channel in three unrelated patients and examined its functional effects. METHODS: The patients (currently aged 2, 8 and 20 years) developed diabetes shortly after birth. The two younger patients attempted transfer to sulfonylurea therapy but were unsuccessful (up to 1.1 mg kg(-1) day(-1)). They remain insulin dependent. None of the patients displayed neurological symptoms. Functional properties of wild-type and mutant channels were examined by electrophysiology in Xenopus oocytes. RESULTS: Heterozygous (het) and homozygous L164P K(ATP) channels showed a marked reduction in channel inhibition by ATP. Consistent with its predicted location within the pore, L164P enhanced the channel open state, which explains the reduction in ATP sensitivity. HetL164P currents exhibited greatly increased whole-cell currents that were unaffected by sulfonylureas. This explains the inability of sulfonylureas to ameliorate the diabetes of affected patients. CONCLUSIONS/INTERPRETATION: Our results provide the first demonstration that mutations such as L164P, which produce a severe reduction in ATP sensitivity, do not inevitably cause developmental delay or neurological problems. However, the neonatal diabetes of these patients is unresponsive to sulfonylurea therapy. Functional analysis of PNDM mutations can predict the sulfonylurea response.
Assuntos
Diabetes Mellitus/genética , Doenças do Recém-Nascido/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Trifosfato de Adenosina/metabolismo , Trifosfato de Adenosina/farmacologia , Adulto , Substituição de Aminoácidos , Animais , Criança , Pré-Escolar , DNA/sangue , DNA/genética , DNA/isolamento & purificação , Diabetes Mellitus/tratamento farmacológico , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipoglicemiantes/uso terapêutico , Recém-Nascido , Modelos Moleculares , Oócitos/fisiologia , Canais de Potássio Corretores do Fluxo de Internalização/química , Canais de Potássio Corretores do Fluxo de Internalização/efeitos dos fármacos , Conformação Proteica , Compostos de Sulfonilureia/uso terapêutico , Xenopus laevisRESUMO
Heterozygous activating mutations in Kir6.2 (KCNJ11), the pore-forming subunit of the adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channel, are a common cause of neonatal diabetes (ND). We assessed the functional effects of two Kir6.2 mutations associated with ND: K170T and E322K. K(ATP) channels were expressed in Xenopus oocytes, and the heterozygous state was simulated by coexpression of wild-type and mutant Kir6.2 with SUR1 (the beta cell type of sulphonylurea receptor (SUR)). Both mutations reduced the sensitivity of the K(ATP) channel to inhibition by MgATP and enhanced whole-cell K(ATP) currents. In pancreatic beta cells, such an increase in the K(ATP) current is expected to reduce insulin secretion and thereby cause diabetes. The E322K mutation was without effect when Kir6.2 was expressed in the absence of SUR1, suggesting that this residue impairs coupling to SUR1. This is consistent with its predicted location on the outer surface of the tetrameric Kir6.2 pore. The kinetics of K170T channel opening and closing were altered by the mutation, which may contribute to the lower ATP sensitivity. Neither mutation affected the sensitivity of the channel to inhibition by the sulphonylurea tolbutamide, suggesting that patients carrying these mutations may respond to these drugs.
Assuntos
Diabetes Mellitus/genética , Mutação/genética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/fisiologia , Trifosfato de Adenosina/fisiologia , Animais , Diabetes Mellitus/fisiopatologia , Condutividade Elétrica , Heterozigoto , Humanos , Recém-Nascido , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização/fisiologia , RatosRESUMO
Several observations suggest an interaction of the sodium channel alpha-subunit with the cytoskeletal structures. However, there is a wide variability in the results of experiments of heterologous expression in Xenopus oocytes and studies on mammalian cells are sometimes contradictory. In general, there has been no direct demonstration that ad hoc large perturbations of the cytoskeleton modify the intrinsic properties of the sodium channels expressed endogenously or heterologously in plasma membranes. We have studied in CHO cells transfected with the rat muscle sodium channel alpha-subunit the effects of two substances expected to produce drastic perturbations of the cytoskeletal structure: Cytochalasin-D, which depolymerizes microfilaments, and Colchicine, which inhibits the microtubules polymerization. We observed no significant differences in the voltage dependence, kinetic parameters and surface density of the expressed sodium channels after treatment of the cells with these substances. We conclude that the two known main components of the cytoskeleton do not interfere directly with the sodium channel function or with the heterologous expression of channels in the cell membrane.