Visceral adipose tissue is an independent correlate of glucose disposal in older obese postmenopausal women.

Older obese postmenopausal women have an increased risk for type 2 diabetes and cardiovascular disease. Increased abdominal obesity may contribute to these comorbidities. There is considerable controversy, however, regarding the effects of visceral adipose tissue as a singular predictor of insulin resistance compared to the other constituents of adiposity. To address this issue, we examined the independent association of regional adiposity and total fat mass with glucose disposal in obese older postmenopausal women. A secondary objective examined the association between glucose disposal with markers of skeletal muscle fat content (muscle attenuation) and physical activity levels. We studied 44 healthy obese postmenopausal women between 50 and 71 yr of age (mean +/- SD, 56.5 +/- 5.3 yr). The rate of glucose disposal was measured using the euglycemic/hyperinsulinemic clamp technique. Visceral and sc adipose tissue areas and midthigh muscle attenuation were measured from computed tomography. Fat mass and lean body mass were estimated from dual energy x-ray absorptiometry. Peak VO2 was measured from a treadmill test to volitional fatigue. Physical activity energy expenditure was measured from indirect calorimetry and doubly labeled water. Pearson correlations indicated that glucose disposal was inversely related to visceral adipose tissue area (r = -0.40; P < 0.01), but not to sc adipose tissue area (r = 0.17), total fat mass (r = 0.05), midthigh muscle attenuation (r = 0.01), peak VO2 (r = -0.22), or physical activity energy expenditure (r = -0.01). The significant association persisted after adjusting visceral adipose tissue for fat mass and abdominal sc adipose tissue levels (r = -0.45; P < 0.005; in both cases). Additional analyses matched two groups of women for fat mass, but with different visceral adipose tissue levels. Results showed that obese women with high visceral adipose tissue levels (283 +/- 59 vs. 137 +/- 24 cm2; P < 0.0001) had a lower glucose disposal per kg lean body mass compared to those with low visceral adipose tissue levels (0.44 +/- 0.14 vs. 0.66 +/- 0.28 mmol/kg x min; P < 0.05). Visceral adipose tissue is an important and independent predictor of glucose disposal, whereas markers of skeletal muscle fat content or physical activity exhibit little association in obese postmenopausal women.

Testosterone and oxandrolone, a nonaromatizable androgen, specifically amplify the mass and rate of growth hormone (GH) secreted per burst without altering GH secretory burst duration or frequency or the GH half-life.

We investigated the mechanisms by which androgens increase mean circulating GH concentrations in boys. We tested two hypotheses: 1) testosterone increases serum GH concentrations at least in part via an androgen receptor-mediated mechanism, rather than exclusively by way of aromatization to estrogen; 2) androgen augments one or more specific features to GH secretion (secretory burst number, amplitude, and/or duration) and/or prolongs the half-life of GH removal. To examine these hypotheses, prepubertal boys with constitutionally delayed development and/or growth were given injections of testosterone (100 mg monthly; n = 7) or treated with oral oxandrolone, a nonaromatizable androgen (1.25 mg twice daily; n = 5). Pulsatile GH release was studied before and during androgen administration by sampling blood at 20-min intervals for 24 h. The immunoreactive GH time series were subjected to a novel deconvolution technique, which revealed that 1) testosterone and oxandrolone each increased mean (24-h) serum GH concentrations significantly; 2) both androgens augmented the daily endogenous GH secretory rate significantly; 3) increased GH production resulted from a higher mass of GH secreted per burst and a higher maximal rate of GH secretion within each burst; and 4) androgens amplified the magnitude of the nyctohemeral rhythm in the mass (but not frequency) of GH secretory pulses. The observed effects of androgen were specific, since the number and duration of GH secretory bursts and the subject-specific GH half-life were unaltered by androgen treatment. We conclude that androgen acting apart from conversion to estrogen is capable of specifically activating the somatotropic axis via distinct neuroendocrine secretory mechanisms.

Trp64Arg variant of the beta3-adrenoceptor and insulin resistance in obese postmenopausal women.

There is controversy regarding the role of the Trp64Arg variant of the beta3-adrenergic receptor (beta3AR) gene in the pathogenesis of insulin resistance. The modest effect of the variant as well as differences in study design, gender, age, and genetic background may contribute to divergent results among investigations. Insulin sensitivity (euglycemic clamp and tracers) was measured in 13 obese women (57 +/- 6 yr old) heterozygous for the beta3AR variant and in 14 women (57 +/- 4 yr old) homozygous for the normal gene. Groups were matched for age, body composition, intraabdominal fat, sc abdominal fat, physical activity level, and aerobic capacity. Exogenous glucose infusion during the clamp was significantly lower (P = 0.03) in beta3AR heterozygotes (241 +/- 135 mg/min) vs. normal homozygotes (379 +/- 172 mg/min). Basal endogenous glucose production was not different (P = 0.20) between heterozygotes (175 +/- 27 mg/min) and normal homozygotes (164 +/- 14 mg/min). Endogenous glucose production during hyperinsulinemia was also not different (P = 0.22) between heterozygotes (77 +/- 57 mg/min) and normal homozygotes (56 +/- 16 mg/min). Total glucose disposal adjusted for residual endogenous glucose production was lower (P = 0.049) for heterozygotes (320 +/- 111 mg/min) than for normal homozygotes (441 +/- 183 mg/min). Our results suggest that obese postmenopausal women who are heterozygous for the Trp64Arg variant in the beta3AR gene have greater insulin resistance than age-, body composition-, and physical activity-matched women homozygous for the normal gene.

Lipolysis in elderly postmenopausal women.

The rate of fat oxidation at rest decreases with age in women. The mechanisms for this decrease are not clear. Theoretically, a decrease in the availability of fatty acids could explain the decline in fat oxidation. In consequence, the in vivo rate of production of fatty acids as a proxy for lipolysis was measured in 21 healthy women. Eleven of the volunteers were elderly (> 65 years) and 10 were young (< 24 years), and all were characterized for body composition. The nonadjusted rate of delivery of fatty acids into the systemic circulation was similar among elderly and young individuals (609 +/- 80.3 v 597 +/- 69.9 mumol/min, respectively, P > .1). When lipolysis was adjusted for the differences in fat-free mass using analysis of covariance (ANCOVA), rates were slightly increased in the elderly group (626 +/- 80 mumol/min) and decreased in the young group (578 +/- 84 mumol/min), but remained nonstatistically significant. It is concluded that mechanisms other than lipolysis must explain the decrease of fat oxidation in aging women, i.e., a decrease in the capacity of muscle to oxidize fat and/or a decrease in its capacity for transport of long-chain fatty acids.

Insulin resistance and type 2 diabetes mellitus: its relationship with the beta 3-adrenergic receptor.

The beta 3 subtype of adrenaline and noradrenaline receptors has been extensively characterized at structural and functional levels. Ligand binding and adenyl cyclase activation studies have helped to define their unique beta-adrenergic profile. Humans, other larger mammals, and rodents share most of the characteristic beta 3-adrenergic receptor properties, although obvious species-specific differences have been identified. Most studies in animal models have shown a distinct beta 3-adrenergic receptor activity that results in an increase in energy expenditure, decrease of fat mass (especially of intra-abdominal fat), and increased glucose disposal efficiency. It is of interest that mild weight increase was shown to develop in female but not male mice, in whom the beta 3-adrenergic receptor gene was disrupted. Recently, the incidence of a naturally occurring variant of the human beta 3-adrenergic receptor was shown to correlate with hereditary obesity in Pima Indians and Japanese individuals. In Western obese patients, this phenotype increased the capacity to gain weight and develop type 2 diabetes mellitus. Studies of humans with the Trp64Arg variant have shown controversial results. Many studies have failed to show any effect in heterozygous male subjects, and only modest effects in homozygous male subjects. In women, several studies have shown modest-to-significant effects regarding weight gain, intra-abdominal fat, and decreased insulin sensitivity in heterozygous and homozygous women. Other studies have failed to show any effect in heterozygous females. Disruptions in the activity of the beta 3-adrenergic receptor in the homozygous male and the heterozygous or homozygous female appear to have a profound effect in animal models, but a limited consequence in human physiology. Association with obesity or diabetes in humans is still controversial. This difference between animal and human models may be explained by the different quantity and distribution of metabolically active brown adipose tissue in the two.

Type 2 diabetes: one disease, multiple cardiovascular risk factors.

Type 2 diabetes mellitus is a major independent risk factor for coronary artery disease. Atherosclerosis accounts for about 80% of all deaths from type 2 diabetes, of which roughly 75% are attributable to coronary artery disease and the remainder to cerebrovascular or peripheral vascular events [1]. The earlier onset and accelerated course of atherosclerosis in individuals with type 2 diabetes mellitus is multifactorial. Type 2 diabetes is associated with abnormalities in lipoprotein metabolism and increased propensity for oxidative damage. The hyperglycemia of patients with type 2 diabetes, in itself, may accelerate vascular damage. Type 2 diabetes is a hypercoagulable state attributable to enhanced coagulation and decreased fibrinolysis, as well as platelet hyperaggregability and endothelial dysfunction. Hypertension is common in individuals with type 2 diabetes and has a major impact in the accelerated atherosclerosis of this disease. This review provides an overview of selected aspects of these alterations.

[Response of insulin and C-peptide to a mixed meal in non-insulin-dependent diabetics treated with insulin and chlorpropamide]. / Respuesta de insulina y péptido C a una comida mixta en diabéticos no insulinodependientes tratados con insulina y cloropropamida.

Glucose control in NIDDM is prone to progressive deterioration due to secondary failure to oral hypoglycemic therapy. Insulin may subsequently be required for optimal control in spite of peripheral hyperinsulinemia. In Mexico, diabetes associated with obesity is common. We therefore designed a prospective study combining insulin and chloropropamide in order to evaluate any improvement in insulin response to a standardized meal load and a consequent amelioration of glucose control. METHODS. Twenty diabetic patients with secondary failure to full doses of hypoglycemic drugs and moderate hyperglycemia were recruited. Therapy was initiated with human insulin 20 IU/day and 500 mg cholopropamide, titrating insulin dosage in order to achieve euglycemia. Before treatment and at the end of the study period, a glucose/insulin/C peptide response curve to a mixed standardized meal was performed. Blood glucose, serum lipids fructosamine and glycosylated hemoglobin levels were also determined. All patients were followed by capillary glucose measurements three times a week and glucose and fructosamine concentrations every two weeks during the study period. RESULTS. All patients required less insulin, and glucose control improved significantly. Glucose, fructosamine and glycosylated hemoglobin levels decreased from 262 mg/dL, 369 mmol/L and 14% to 111 mg/dL, 252 mmol/L, and 8% respectively; all differences were statistically significant. Insulin and C peptide levels increased significantly from 22.2 mU/mL and 1.65 ng/mL to 29.8 mU/mL and 1.97 ng/mL, respectively. When we measured the area under the curve, total values improved from 110 and 7.69 to 127 and 9.37, respectively; this was also statistically significant. Lipids levels decreased significantly, including triglicerides, total and LDL cholesterol whereas HDL cholesterol levels increased. CONCLUSIONS. Glucose control improved in our patient cohort the pancreatic insulin response probably due to a more adequate glycemic microenvironment and a possible enhanced exogenous and endogenous insulin function.

[The use of antibiotics at the outpatient clinic of the "Salvador Zubirán" National Institute of Nutrition]. / Uso de antibióticos en la consulta externa del Instituto Nacional de la Nutrición "Salvador Zubirán".

We conducted a survey of the prescription of antibiotics among the outpatient clinics of the Instituto Nacional de la Nutrición "Salvador Zubirán", a third level hospital in México City. We made an auditory of the medical record and prescriptions given to every patient treated for an infectious episode, accounting for at least six questions to evaluate the quality of the prescription: 1) if the patient should had received antibiotics; 2) if the antibiotic prescribed was adequate; 3) if the dose was sufficient; 4) if the frequency of administration was correct; 5) if the route of administration was adequate; and 6) if the length of the treatment was sufficient. We validated the concordance among two evaluators and found that it was 89% for the whole questionnaire. In the evaluation we found that the patients should had received antibiotic 94% of the time: the antibiotic selected was a right choice 80% of the time; the dose was adequate 45% of the time; the frequency of administration was adequate 70% of the time; the route of administration was adequate 79% of the time; and the length of treatment was adequate 38% of the time. The worst findings were seen in two of the most important issues of antibiotic prescription which directly affect the appearance of antibiotic resistance.

[Thyroid nodule. Study of 88 cases]. / Nódulo tiroideo. Estudio de 88 casos.

We present a prospective study of 88 patients with thyroid nodules seen in our institution in 1985-86 and the results of a 5 year follow up. The algorithm for resolution among different therapeutic options was established in regard to the clinical characteristics, imaging and particularly the histopathologic studies. Their age ranged from 18 to 79 years; 94% of the patients were females. Most of the nodules were solid (69%) and measured 1-4 cm in diameter. The image of 62% of the thyroid scans was of a non-functioning nodule and 13% were hyperfunctioning. In 80% the ultrasonographic pattern was solid or mixed. Surgery was undertaken in 19 patients (21%). In 58%, a diagnosis of malignancy was established. The biopsy (aspiration and tru-cut) suggested the presence of the malignant tumors when taken together in 90% of the cases. Hormonal treatment was given to 62 patients; in 40-45% of them there was a significant reduction in the size of the nodule. Aspiration and sclerosis of cystic nodules were performed in 19 patients with significant shrinkage in 82%. Radioactive iodine was used in 11 patients. Our algorithm reduces costs and precludes unnecessary morbidity in patients with thyroid nodules.

[Late complication of diabetes mellitus of pancreatic origin]. / Complicaciones tardías de la diabetes mellitus de origen pancreático.

At Instituto Nacional de la Nutrición SZ in Mexico City, we reviewed 30 years of experience and selected 46 patients with Pancreatic Diabetes (PD), without family history of Diabetes Mellitus (DM) with at less two years of follow-up. Alcoholic chronic pancreatitis (CP) was found in 36 patients, in seven it was idiophatic and in three was secondary to pancreatectomy. We compared the evolution of this patients with a group of (DM) patients similar in age, sex, glucemic control and time of onset. There were no statistical differences between groups in the follow-up of diabetic complications, only it was found a tendency to have higher lipid levels, macroangiopathy and retinopathy in those with DM. We concluded that CP have similar evolution as DM and could have deleterous complications in the large follow up.

[Premature atherosclerosis in a 17-year-old male with diabetes mellitus and familial dyslipoproteinemia]. / Aterosclerosis prematura en un joven de 17 años con diabetes mellitus y una dislipoproteinemia familiar.

A 17-year-old male was admitted with an acute myocardial infarction. A coronarography showed 90% occlusion in of the descendent anterior artery. A coronary angioplasty was done with excellent response. As coronary risk factors he had diabetes mellitus for 5 years and dyslipidemia with a phenotype IIb and hypo-alpha-lipoproteinemia. The case is discussed in regard to the possible etiopathogenic causes for his premature atherosclerosis.

[Non-insulin-dependent diabetes mellitus increases early mortality due to acute myocardial infarct]. / La diabetes mellitus no dependiente de insulina incrementa la mortalidad temprana por infarto agudo del miocardio.

Previous reports suggest that morbidity and mortality post acute myocardial infarction (AMI) are increased in patients with non-insulin-dependent diabetes (NIDDM). To obtain information in our population related to the prognosis after an AMI in diabetic patients and its major determinants, we studied 96 NIDDM patients admitted consecutively with a diagnosis of AMI. We used a control group (CG) of age and sex matched non-diabetic individuals. Patients with NIDDM had more frequently a history of angina (40 vs 23%, p < 0.001) and previous MI (30 vs 15%, p < 0.05). The AMI localization and extension, and the presence of arrhythmias were similar for both groups. Early mortality after the AMI was 22% in the NIDDM group and 12% in the CG with Odds ratio of 1.9 (CI 95% 0.91-5.15), being higher in diabetic females [2.3 (CI 95% 0.77-14.6) vs female CG and 1.5 (CI 95% 0.8-7.6) vs male NIDDM]. Extended MIs predicted higher mortality rate, especially among NIDDM patients (p < 0.05). Stepwise logistic regression test supported diabetes mellitus, per se, as a major contributor for mortality (p < 0.02), followed by MI localization and extension. The worst outcome was in NIDDM female patients of advanced age and hypertensive (p < 0.00001).

[The efficacy of cholestyramine as a hypocholesterolemic agent and its tolerance in a Mexican population]. / Eficacia como agente hipocolesterolemiante y tolerancia de la colestiramina en población mexicana.

The tolerance and efficacy of cholestyramine (12-16 gr/day) was evaluated in 19 patients with primary type-IIa hyperlipoproteinemia. All patients were on an isocaloric low-cholesterol diet that began at least one month before entry, and was continued during the eight weeks of the study. Cholestyramine significantly (p less than 0.001) lowered the plasma levels of cholesterol and of low density lipoprotein cholesterol from means of 288 +/- 46 mg/dl to 244 +/- 44 mg/dl and from 221 +/- 50 mg/dl to 171 +/- 46 mg/dl respectively. These were reductions of 15 and 22%. The magnitude of response to cholestyramine was unrelated to age, sex, cause of the hypercholesterolemia (familial or polygenic) or basal cholesterol levels. The drug was well tolerated. Only one patient was excluded because gastrointestinal discomfort. Because of its safety and efficacy, cholestyramine can be recommended as a first choice drug in the treatment of hypercholesterolemia.

The effects of opioid blockade and GnRH administration upon luteinizing hormone secretion in patients with anorexia nervosa during the stages of weight loss and weight recovery.

OBJECTIVE: We examined the functional status of the hypothalamic-opioid system involved in LH secretion and the pituitary LH sensitivity and reserve in patients with anorexia nervosa were studied during body weight loss and weight recovery. We measured the temporal relationship between weight recovery, expression of hypothalamic-opioid activity and pituitary GnRH responsiveness, and resumption of ovulatory cycles. DESIGN: Five patients with anorexia nervosa were prospectively studied during weight loss and amenorrhoea, subsequently when they reached their ideal body weight but still remained amenorrhoeic and thereafter every 6 months until resumption of ovulatory cycles; one patient was studied only during weight loss, two during ideal body weight and amenorrhoea and one during ideal body weight and ovulatory cycles. Blood was sampled every 10 minutes over a 16-hour period on two alternate days. On study day 1 (control day), patients received two sets of saline infusion every 6 hours and one saline bolus at the beginning of the seventh hour; on study day 3 (experimental day), they received a saline infusion during the first 6 hours, an intravenous bolus of naloxone (20 mg) at the beginning of the seventh hour and then a continuous naloxone infusion (1.6 mg per hour) during the ensuing 6 hours. Pituitary LH sensitivity and reserve were assessed on both study days by the subsequent administration of 5 and 95 micrograms of GnRH 4 hours before the completion of each sampling period. Patients in ideal body weight and ovulatory cycles as well as five normal menstruating women included in the study for comparative purposes, were studied during the midluteal phase of a cycle. MEASUREMENTS: LH, oestradiol and progesterone were determined by radioimmunoassay. Areas under the LH curve were calculated by the trapezoid method; LH pulse detection was carried out by the program Cluster. RESULTS: Naloxone administration to patients with anorexia nervosa in the weight loss phase, did not significantly modify their serum LH levels nor the characteristics of its pulsatile secretion. Administration of the opioid blocker induced a significant increase in serum LH concentrations only in those patients in ideal body weight and amenorrhoea who resumed ovulatory cycles within the 6 months following the last study as well as in patients with an ideal body weight and ovulatory cycles and in normal controls. All patients and subjects who responded to naloxone administration exhibited significant increases in the area under the LH curve, mean LH pulse amplitude and peak area. Patients in ideal body weight and amenorrhoea who did not resume ovulatory cycles within the 6 months following the study days, did not respond to naloxone administration. There were no significant correlations between the magnitude of LH response to naloxone administration and the baseline levels of serum oestradiol and progesterone. All patients exhibited significant pituitary LH responses to both GnRH doses, regardless of the stage of the disease; however, the pituitary responsiveness shown by patients in ideal body weight was significantly higher than that presented by patients in weight loss. There were no significant differences between the responses to GnRH exhibited by patients in ideal body weight and amenorrhoea who responded to naloxone administration and those shown by patients in the same clinical condition but who were insensitive to opioid blockade. CONCLUSIONS: The re-establishment of hypothalamic-opioid inhibitory activity involved in LH secretion in patients with anorexia nervosa during the phase of weight gain predicts imminent restoration of ovulatory cycles. Pituitary LH response to exogenous GnRH during weight recovery does not accurately predict the outcome of the disease regarding reinitiation of menstrual cycles; however, it might be an indicator that the normal function of the hypothalamic-pituitary axis is being restored.

Eficacia del acetaminofen en el posoperatorio de cirugia de torax. / Efficacy of acetaminophen in the postoperative care of thoracic surgery

En el Servicio de Terapia Intensiva del Instituto Nacional de Enfermedades Pulmonares en Tlalpan, D.F., se estudio una muestra de 75 pacientes con objeto de valorar la eficacia de la accion analgesica del acetaminofen tabletas 500 mg, comparada con la dipirona sodica 500 mg y acido ascorbico 500 mg. Los diagnosticos de los enfermos que integraron el estudio corresponden a posoperatorio de cirugia maxilofacial, cirugia de torax; biopsia pulmonar, descorticacion pleural, plastia de lobulo, neumonectomia, toracoplastia y lavado de cavidades. La valoracion del dolor no es facil, para el efecto se utilizo el metodo propuesto por Melzack y Scott. El alivio del dolor posoperatorio severo fue obtenido con acetaminofen de uma manera mas rapida y prolongada que con la dipirona. Esto concuerda con los estudios de Bonilla y de Lopez Mariche. En nuestro estudio acetaminofen fue estadisticamente significativo en un nivel de p > 0.001. Noventa y cinco por ciento de los pacientes fueron beneficiados con el uso del acetaminofen, controlandose en ellos el dolor agudo de manera mas eficiente y prolongada que con el empleo de la dipirona. Durante el estudio no se encontraron efectos colaterales