Adalberto Parra

Contribution of Common Genetic Variation to the Risk of Type 2 Diabetes in the Mexican Mestizo Population

Several studies have identified nearly 40 different type 2 diabetes susceptibility loci, mainly in European populations, but few of them have been evaluated in the Mexican population. The aim of this study was to examine the extent to which 24 common genetic variants previously associated with type 2 diabetes are associated in Mexican Mestizos. Twenty-four single nucleotide polymorphisms (SNPs) in or near genes (KCNJ11, PPARG, TCF7L2, SLC30A8, HHEX, CDKN2A/2B, CDKAL1, IGF2BP2, ARHGEF11, JAZF1, CDC123/CAMK1D, FTO, TSPAN8/LGR5, KCNQ1, THADA, ADAMTS9, NOTCH2, NXPH1, RORA, UBQLNL, and RALGPS2) were genotyped in Mexican Mestizos. A case-control association study comprising 1,027 type 2 diabetic individuals and 990 control individuals was conducted. To account for population stratification, a panel of 104 ancestry-informative markers was analyzed. Association to type 2 diabetes was found for rs13266634 (SLC30A8), rs7923837 (HHEX), rs10811661 (CDKN2A/2B), rs4402960 (IGF2BP2), rs12779790 (CDC123/CAMK1D), and rs2237892 (KCNQ1). In addition, rs7754840 (CDKAL1) was associated in the nonobese type 2 diabetic subgroup, and for rs7903146 (TCF7L2), association was observed for early-onset type 2 diabetes. Lack of association for the rest of the variants may have resulted from insufficient power to detect smaller allele effects.

Effect of the diagnostic criteria of the International Association of Diabetes and Pregnancy Study Groups on the prevalence of gestational diabetes mellitus in urban Mexican women: a cross-sectional study.

OBJECTIVE To explore the prevalence of gestational diabetes mellitus (GDM), defined by the previous criteria of the American Diabetes Association (ADA), as well as the criteria suggested by the International Association of Diabetes and Pregnancy Study Groups (IADPSG), in an unselected group of urban Mexican pregnant women and to analyze the frequency of large for gestational age (LGA) newborns in this same group of women with use of both diagnostic criteria. METHODS A cross-sectional study included 803 consecutive Mexican urban women with a singleton pregnancy, without concomitant diseases and no prior history of GDM, who underwent a 2-step screening protocol for diagnosis of GDM at admission to prenatal care. RESULTS The ADA criteria identified 83 women (10.3%) whereas the IADPSG criteria diagnosed 242 women (30.1%) having GDM (P = .0001). Fasting glucose concentrations during the 100-g 3-hour oral glucose tolerance test were abnormal in 116 women (14.4%) and in 160 women (19.9%) on the basis of ADA and IADPSG criteria, respectively (P = .004). The frequency of LGA newborns was 7.4% based on IADPSG criteria and 6.0% based on ADA criteria-no significant difference (P = .64). CONCLUSION With use of the IADPSG criteria, the prevalence of GDM increased almost 3-fold in comparison with that for the ADA criteria. Nevertheless, no significant difference was found in the prevalence of LGA newborns.

Overgrowth of Lean and Adipose Tissues in Adolescent Obesity

Extract: In 14 obese females and 9 obese males, body length was used as a base line for the detection of excess growth of lean and adipose tissue.Eighteen patients had increased lean body mass based on body water determinations (fig.1), and 40K was found to be an unreliable diagnostic agent for the prediction of lean body mass. A similar number of patients had excessive amounts of intracellular mass (fig.2). Males had an increment in total protein content within the adipose tissue mass (table IV), whereas half of the females (and all those possessing advanced bone age) had increments in muscle mass (fig.3) and in the DNA content of their musculature (fig.4). A sufficient number of female patients were studied to document two classes of obesity—one group with, and one group without advanced maturation, excess nuclei (fig.4), and reduced protein/DNA (fig.5) in the musculature.Studies of noncollagen protein in adipose tissue mass of male subjects indicated an increase in the number of adipocytes compared with those found in normal or obese females (table IV). In addition, protein and water concentrations of adipose tissue were reduced in all the obese patients studied (table III). The extracellular volume was found to be constant at 17% of body weight in obese adolescent males.Speculation: Obesity in adolescents is the result of genetic, environmental, nutritional, and hormonal factors. Over-nutrition in infancy influences hormonal secretion and produces advanced maturation and excessive cell growth in muscle (as found in this study in one group of obese females). Also, in one group of obese females, estrogens, which retard cell number increase (in the normal pubertal female), are possibly suppressed by androgens and thus allow androgen and growth hormone to exert maximal effects at the muscle level (increase of cell number).In the obese male, the superimposition of high levels of circulating insulin on androgen secretion enhances the growth of collagen and of adipocytes in the adipose tissue mass. Thus, the particular changes in body composition occurring in obesity are dependent on the sex of the individual.

Correlative Studies in Obese Children and Adolescents Concerning Body Composition and Plasma Insulin and Growth Hormone Levels

Extract: Levels of plasma insulin, growth hormone (HGH), glucose, and free fatty acids (FFA) were investigated in 17 obese, nondiabetic children or adolescents after administration of intravenous arginine, oral glucose, and a protein-glucose meal. These results were compared with those obtained in eight normal adolescents. Four of the obese patients had a family history of diabetes but had hormonal responses identical with those observed in obese subjects with a negative family history of diabetes. Subjects were arbitrarily separated into two groups depending on duration of obesity (Table I) (age of onset was different: infancy or early childhood for group B, 5–8 years for group A). Subjects in group B (longstanding obesity) all had a strong family history of obesity with marked increases in body weight, body fat, and excess fat. Fasting levels of insulin were greater than normal (P < 0.001 (Table II)). Patients in group A (short duration), with lesser increments in body weight and body fat, had normal fasting levels of insulin and normal response to intravenous arginine (Fig. 4). All obese subjects had hyperinsulinemia in response to other stimuli, but patients in group B achieved the highest insulin levels (Figs. 2, 3, and 4). All obese patients had significantly decreased levels of HGH during tests and elevated fasting levels of FFA. Patients in group B exhibited a reduced mean decrement in FFA during the oral glucose tolerance test.Whether or not responses seen in patients in group A represent an early stage of the conditions observed in patients in group B cannot be determined by this study, but the biochemical changes reported in established obesity of childhood mimic those found in the adult.Speculation: Obesity in children is associated with excess lipogenesis and hyperinsulinemia, which are interdependent and initiated through maximal nutritional intake in infancy.Eventually muscle becomes resistant to insulin with decreased transport of glucose into the cell and decreased protein synthesis relative to DNA. The reduced levels of growth hormone in the circulation may indicate excessive uptake by muscle, which is followed, in some instances, by an associated proliferation of nuclei.

Differential prolactin response to oral metoclopramide in nulliparous versus parous women throughout the menstrual cycle

OBJECTIVE To analyze if serum prolactin (PRL) changed throughout the menstrual cycle and if parous women have lower PRL than nulliparous women. DESIGN A prospective study of PRL was performed in basal conditions and during oral metoclopramide stimulation on days 7, 14, and 21 of menstrual cycle. SETTING Instituto Nacional de Perinatología, third level medical institution. PATIENTS Four parous (group A) and seven nulliparous (group B) healthy volunteer women entered and finished the study. INTERVENTIONS Women were studied each day before and every 30 minutes during 2 hours after oral metoclopramide (10 mg). MAIN OUTCOME MEASURE Duplicate PRL determinations were performed by radioimmunoanalysis. Hypothesis was formulated before data collection. RESULTS Group A and B had similar basal PRL levels and no within group differences existed in response to metoclopramide, regardless of the day studied. Group A had lower PRL increments than group B from 60 to 120 minutes on days 14 and 21 (P less than 0.05); the peak increments also were lower on days 7, 14, and 21 (P less than 0.05). CONCLUSIONS Parous women had a diminished PRL response. Although the dopaminergic tone was similar throughout the menstrual cycle within each group, two distinct levels of dopaminergic tone existed in parous and nulliparous women.

Hypothalamic Dopaminergic Tone and Prolactin Bioactivity in Women with Polycystic Ovary Syndrome

BACKGROUND The present study was carried out to investigate the functional significance of the reduced dopaminergic tone in subjects affected with polycystic ovary syndrome (PCOS). METHODS Our group evaluated the response of pituitary PRL, LH, FSH, and TSH to the administration of a single 10-mg oral dose of the dopamine (DA) receptor antagonist metoclopramide in lean (n = 7) and obese (n = 8) PCOS women and in 11 regularly cycling age- and weight-matched controls (six lean and five obese). In addition, circulating PRL bioactivity was evaluated by its mitogenic activity on a lymphoma cell bioassay. RESULTS Oral administration of metoclopramide resulted in a significant increase in serum PRL in all subjects; however, the highest increments, regardless of body mass index (BMI), were observed in control women (p <0.005). Measurements of PRL mitogenic activity on the Nb2 lymphoma cell bioassay revealed a significant increase in the bioactive/immunoreactive (B/I) ratio of PRL under basal and stimulated conditions in obese PCOS subjects (p <0.05). Mean fasting glucose/insulin and glucose/insulin-AUC ratios were significantly lower (p <0.001) in obese PCOS when compared with all other groups. CONCLUSIONS These data support the existence of low DA hypothalamic tone in PCOS women that is likely involved in the inappropriate LH and PRL secretion frequently seen in this syndrome. In addition, our results suggest changes in PRL bioactivity in obese PCOS that may play a role in the development of hyperinsulinemia; however, whether PRL has a functional significance in the development of the metabolic disturbances frequently seen in PCOS remains to be elucidated.

The risk of gestational diabetes mellitus among Mexican women with a history of infertility and polycystic ovary syndrome.

OBJECTIVE To study the incidence of gestational diabetes mellitus (GDM) in Mexican women with a history of infertility and polycystic ovary syndrome (PCOS) compared with women without PCOS matched by age, pregestational body mass index (BMI), and parity. DESIGN Historic cohort study. SETTING Level three medical institution. PATIENT(S) Group 1 (n = 52), women with a history of infertility and PCOS, and group 2 (n = 52), women without PCOS. Inclusion criteria were singleton pregnancy with ≤ 13 weeks of gestation. Exclusion criteria were pregestational diabetes mellitus and/or concomitant diseases. INTERVENTION(S) Diagnosis of GDM was based on a 3-hour, 100-g oral glucose tolerance test (GTT) performed during the second trimester. MAIN OUTCOME MEASURE(S) Incidence and relative risk (RR) for GDM. RESULT(S) The incidence of GDM was 26.9% and 9.6% for groups 1 and 2, respectively (RR = 2.8; 95% confidence interval 1.08-7.2). No other between-group differences were observed in the incidence of miscarriage, preterm birth, premature rupture of membranes, preeclampsia, stillbirth, fetal malformations, or small or large for gestational age newborns. CONCLUSION(S) Pregnant Mexican women with a history of infertility and PCOS are at increased risk for developing GDM. This risk should be considered beginning early in the second trimester for a timely intervention and to improve the maternal-fetal prognosis.

The after breakfast 50-g, 1-hour glucose challenge test in urban Mexican pregnant women, Its sensitivity and specificity evaluated by three diagnostic criteria for gestational diabetes mellitus

BACKGROUND To study the sensitivity and specificity of the 50-g, 1-hour gestational glucose challenge test performed 1 to 2 hours after a non-standardized home breakfast in urban Mexican women by using three different gestational diabetes mellitus diagnostic criteria. METHODS Four hundred and forty-five consecutive women of 24-28 weeks gestation were studied. The glucose challenge test was performed in the fed state and a week later a fasting 100-g, 3-hours oral glucose tolerance test was carried out in all of them. Duplicate serum glucose concentrations were determined by a glucose-oxidase method. Sensitivity and specificity were calculated using three different diagnostic criteria for gestational diabetes mellitus. RESULTS The glucose challenge test performed as indicated, with a cutoff of 7.8 mmol/L, had 88-89% sensitivity and 85-87% specificity when using as diagnostic criteria those proposed by the National Diabetes Data Group and by Carpenter & Coustan; by using Sacks et al. criteria, the values were 82% and 88%, respectively. Considering only pregnant women > or = 25 years of age, the sensitivity increased to 92% with the National Diabetes Data Group criteria. Pregnant women < 25 years of age had significantly lower blood glucose values than those with age > or = 25 years during the glucose tolerance test. CONCLUSIONS For the general group the sensitivity of the glucose challenge test performed 1 to 2 hours after breakfast was similar, based on the National Diabetes Data Group and the Carpenter & Coustans diagnostic criteria for gestational diabetes mellitus. However, when pregnant women > or = 25 years of age were considered, the use of the former criteria yielded a slightly better sensitivity.

Propranolol effect on plasma glucose, free fatty acid, insulin, and growth hormone in Graves' disease.

A 3-hr glucose tolerance test was performed in 12 thyrotoxic patients before and after propranolol treatment for 30 days (120 mg/day). Plasma glucose, free fatty acid, insulin, and growth hormone levels were determined on each test and compared to each other and against nine clinically healthy volunteers. In eight thyrotoxic patients (subgroup A) an improvement in carbohydrate tolerance was observed after propranolol treatment, along with a fall in the previously elevated fasting FFA; no change in plasma insulin levels was observed. Plasma growth hormone levels were higher than normal both before and after propranolol; however, a 46% glucose-induced suppression was seen in both instances. In the other four patients (subgroup B) (who had had a marked and rapid weight loss) a deterioration of the previously normal glucosnificant changes in insulin levels. Elevated fasting plasma free fatty acids remained so despite propranolol treatment. Plasma growth hormone was higher than normal before and after propranolol; a late suppression (at 120 min) and no suppression at all were seen, respectively. After propranolol treatment, subgroup B had higher plasma free fatty acid than subgroup A in the fasting state and at 30 and 180 min. It is proposed that the improvement or deterioration in carbohydrate tolerance after propranolol treatment might be related to whether or not a satisfactory propranolol-induced lipolytic blockade is achieved, leading to a decrease in plasma free fatty acid levels, improved insulin sensitivity, and better peripheral glucose utilization. Therefore, a uniform dose of propranolol will not always be sufficient to obtain adequate lipolytic blockade, particularly if the thyrotoxic patient has had a marked and rapid weight loss.

Relationship between body composition and insulin and growth hormone responses in obese adolescents.

The clinical characteristics and predicted body composition of ten obese nondiabetic and six normal adolescents were compared in regard to plasma insulin, growth hormone, glucose, free fatty acids and alpha-amino nitrogen in response to different stimuli. Analysis of the data suggested the presence of two groups of patients. In obese Group A there was no family history of obesity, the youngsters first became obese between seven to twelve years of age, had a normal height for age, moderate increase in body weight and estimated total body fat, and normal or less than normal fasting levels of insulin. In obese Group B there was a strongly positive family history of obesity, the subjects became obese in infancy or early childhood, they were tall for their age, had marked increase in total body weight and total body fat as well as significantly higher than normal fasting insulin levels. Hyperinsulinemia was present in Group A during the oral glucose tolerance test and protein glucose meal. Normal insulin responses were observed during the protein meal and the arginine tolerance test. On the other hand, Group B manifested hyperinsulinemia in response to all stimuli. Both obese groups had undetectable plasma growth hormone levels during both the protein and the protein-glucose meal, but normal growth hormone responses during the oral glucose and the arginine tolerance tests. The differences in plasma levels of glucose and free fatty acids were minimal. Significant differences in plasma alpha-amino nitrogen values were observed during the protein-glucose meal. Differences in the hormonal responses of obese adolescents and adults are discussed. Possible explanations for heterogeneous responses of obese adolescents are presented.