Association of traits of metabolic syndrome with glucose abnormalities.

The association of glucose abnormalities (GAs) with the early appearance of traits of the metabolic syndrome (MS) was studied in an unselected sample of apparently healthy Urban Hispanics. GAs were defined as impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and newly diagnosed diabetes mellitus (DM). Overall, GAs were associated with older age, abdominal obesity, low high-density lipoprotein cholesterol levels, hypertriglyceridemia, hyperinsulinemia, hypertension, and MS. Prevalence of MS defined as per NCPE-ATPIII was the greatest in subjects with DM (54.3%) and with combined abnormalities (IFG + IGT) (54.1%; P > 0.5). Similar prevalence of MS was found in subjects with isolated IFG (34.3%) and isolated IGT (36.8%) but higher than in normal fasting-glucose tolerant individuals (23.3%) (P < 0.01). The average number of traits of the MS coexisting in normal fasting glucose-tolerant individuals was 1.6 [95% confidence interval (CI), 1.5-1.8; median 2], in isolated IFG: 2.05 (95% CI, 1.8-2.2; median 2); isolated IGT: 2.16 (95% CI, 1.8-2.3; median 2); combined IFG + IGT: 2.7 (95% CI, 2.3-3.1; median 3); and DM: 2.7 (95% CI, 2.25-3.1; median 3) (P < 0.01). Postload insulin levels were higher in isolated IGT than in isolated IFG, whereas HOMA-IR was higher in IFG. Indices of early and total insulin secretion were markedly reduced in DM, IFG-IGT, and IGT. In conclusion, GAs are strongly associated with the number and severity of traits of the MS, defects in insulin secretion, and sustained hyperinsulinemia in response to oral glucose. Subjects with combined GA and newly diagnosed type 2 DM had not only an increased prevalence of MS, but also the MS was characterized by the presence of more than 3 traits, and by a greater severity of each of the coexisting traits.

Prevalence of glucose abnormalities and diagnostic value of fasting glucose and fasting insulin in urban Hispanics.

The prevalence of glucose abnormalities (GAs) and the diagnostic value of fasting plasma glucose and insulin in detecting impaired glucose tolerance (IGT) and diabetes mellitus (DM) were determined in urban Latin Americans. An oral glucose tolerance test was conducted in 592 subjects after administration of 75 g of glucose. Employing American Diabetes Association (ADA) and World Health Organization guidelines, GAs were found in 34% of the subjects, defined as impaired fasting glucose (IFG) (13.3%), IGT (6.9%), combined IFG + IGT (7.8%), and newly diagnosed type-2-DM (6.5%). All newly diagnosed diabetics had 2-hour glucose levels ≥200 mg/dL, but only 46.1% had fasting glucose ≥126 mg/dL. In addition, nearly half of the subjects with IGT (47%) had fasting glucose levels <100 mg/dL. The sensitivity, specificity, positive and negative predictive values of IFG in predicting IGT was 52.9%, 83%, 36.8%, and 90.4 %, respectively. Fasting insulin levels were not sensitive for differentiating glucose tolerant, from IFG and IGT; only the subjects with combined IFG + IGT had increased fasting insulin levels (22% above IFG) (P < 0.01). Two-hour insulin was increased by 30% in IGT and newly diagnosed diabetics, and by 46% in the subjects with combined IFG + IGT. In summary, the very high prevalence of undetected GA encountered in "healthy" subjects living in Caracas, Venezuela, requires immediate sanitary attention. With 50% of diabetic patients being unaware of their condition, half of IGT and DM not detected by ADA guidelines, and the poor sensitivity/specificity of fasting glucose in predicting 2-hour abnormalities, we recommend that 2-hour postload glucose be included when screening for GAs. Measurements of fasting and/or postload insulin are not cost effective for the diagnosis of GA, because they provide little additional clinical information in this context.

Climate change and the characterization, breeding and conservation of animal genetic resources.

Livestock production both contributes to and is affected by climate change. In addition to the physiological effects of higher temperatures on individual animals, the consequences of climate change are likely to include increased risk that geographically restricted rare breed populations will be badly affected by disturbances. Indirect effects may be felt via ecosystem changes that alter the distribution of animal diseases or affect the supply of feed. Breeding goals may have to be adjusted to account for higher temperatures, lower quality diets and greater disease challenge. Species and breeds that are well adapted to such conditions may become more widely used. Climate change mitigation strategies, in combination with ever increasing demand for food, may also have an impact on breed and species utilization, driving a shift towards monogastrics and breeds that are efficient converters of feed into meat, milk and eggs. This may lead to the neglect of the adaptation potential of local breeds in developing countries. Given the potential for significant future changes in production conditions and in the objectives of livestock production, it is essential that the value provided by animal genetic diversity is secured. This requires better characterization of breeds, production environments and associated knowledge; the compilation of more complete breed inventories; improved mechanisms to monitor and respond to threats to genetic diversity; more effective in situ and ex situ conservation measures; genetic improvement programmes targeting adaptive traits in high-output and performance traits in locally adapted breeds; increased support for developing countries in their management of animal genetic resources; and wider access to genetic resources and associated knowledge.

Salt and the metabolic syndrome.

BACKGROUND AND AIMS: High blood pressure in subjects with the metabolic syndrome (MS) is largely related to dietary salt. We investigated in free-living men and women whether increase in dietary salt intake is associated with the presence and severity of the MS. METHODS AND RESULTS: A total of 766 subjects (251M, 515F) of 44.9+/-0.5 years/age and SBP/DBP of 120+/-0.6/77+/-0.4 mmHg were studied. Twenty-four hour urinary sodium (UNa(+)) and potassium (UK(+)) excretions were 143+/-2.5 mmol (median: 131.5) and 48+/-0.9 mmol (median: 44). UNa(+) was higher in men than in women (median: 155.5 vs. 119.8 mmol/day; P<0.0001). UK(+) (r=0.34; P<0.0001), measures of obesity (r=0.26; P<0.0001) and BP (r=0.15; P<0.0001) were significantly associated with UNa(+). The association with BP was lost after adjusting for weight. Of the 766 subjects, 256 (33.4%) met the NCEP-ATPIII criteria for the MS. Median UNa(+) in men and women with no traits of the MS was 140 and 116.7 mmol/day, respectively (P<0.001), increasing to 176 in men and 135 mmol/day in women with 4-5 components of the syndrome (P<0.001). Weight, BMI and waist increased significantly across the quartiles of UNa(+) both in men and women; whereas, age, lipids and fasting glucose did not. SBP and DBP were associated with UNa(+) in men but not in women. UK(+) correlated with age in men and women (r=023; P<0.0001) and with obesity in women (r=0.14; P=0.001). CONCLUSIONS: UNa(+) a measure of dietary sodium intake in free-living subjects was markedly increased in subjects with the MS. Higher UNa(+) was associated with obesity and higher BP, but not with age, dyslipidemia or fasting glucose.

Lowering the threshold for defining microalbuminuria: effects of a lifestyle-metformin intervention in obese "normoalbuminuric" non-diabetic subjects.

BACKGROUND: We investigated whether levels of albuminuria (urinary albumin excretion (UAE)) below those conventionally accepted as microalbuminuria (<30 mg/day) are sensitive to correction of obesity and obesity-related risk factors. METHODS: The effects of a 12-month lifestyle modification-metformin program were evaluated in otherwise healthy overweight/obese "normoalbuminuric" subjects: group I with UAE of <10 mg/day (n = 23) and group II with UAE of 10-29 mg/day (n = 18). RESULTS: The subjects of group II were older and heavier, and had higher blood pressure (BP) and lower high-density lipoprotein (HDL) levels, than those of group I. Creatinine clearances were also higher in group II (148 +/- 14 ml/min) than in group I (108 +/- 9 ml/min). Although the intervention induced comparable reductions in obesity, BP, lipids and insulin levels in both groups, UAE was significantly reduced in group II (9.1 +/- 1.8 mg/24 h; 60% reduction; P < 0.001), and non-significantly in group I (0.75 +/- 0.5 mg/day; 12% reduction; P > 0.1). Additionally, greater reduction in creatinine clearance was observed in subjects with higher UAE rates. After the intervention, both groups achieved similar UAE rates (5.7 +/- 0.9 and 5.2 +/- 1.0 mg/day; P > 0.10). Basal UAE was related to the subjects' creatinine clearance (r = 0.38; P = 0.04). For both groups together, intervention-induced changes in UAE rates were not significantly related to BP, age, or body weight. However, for group II subjects, BP and UAE reduction were positively associated (r = 0.44; P = 0.03). CONCLUSIONS: UAE of 10-29 mg/day (hyperalbuminuria), below the conventionally used limit to define microalbuminuria, is already associated with a more adverse cardiovascular risk profile, and is exquisitely sensitive to interventions that reduce obesity, BP, and insulin resistance.

Salt-resistant and salt-sensitive phenotypes determine the sensitivity of blood pressure to weight loss in overweight/obese patients.

High blood pressure (BP) is extremely common in persons with obesity. However, not all obese individuals have high BP, nor does weight loss lower BP in all persons. In this study, the authors investigated whether the salt-sensitive (SS) or salt-resistant (SR) phenotype determines the degree of BP lowering induced by weight loss in a group of middle-aged individuals of whom 80% are of Hispanic descent. Overweight/obese participants classified as SS or SR (N=45; body mass index, 27-35 kg/m(2)) entered a 1-year program of dietary restriction, aerobic exercise, and metformin therapy. Comparable reductions in obesity (8%-10%), triglycerides (25%), and fasting insulin concentrations (40%) were observed in SR and SS individuals. In SS patients, the intervention lowered systolic BP/diastolic BP by 8.8/6.1 mm Hg, decreased albuminuria by 63%, and decreased the patient's salt sensitivity. Neither BP nor albuminuria was modified in SR persons by the intervention. In obese SS individuals, salt restriction induced comparable BP lowering as weight reduction. In summary, BP lowering induced by the lifestyle/metformin intervention appears to be determined by the SR/SS phenotype. Weight loss and correction of metabolic abnormalities lowers BP in obese SS persons but not in obese SR persons. Correcting adiposity in SS patients lowers BP by making the BP insensitive to dietary salt. The SR phenotype protects from obesity-induced increases in BP.

CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity.

Reduced adrenal 11 beta-hydroxylation has been associated with an aldosterone synthase (CYP11B2) polymorphism. The 11 beta-hydroxylase gene (CYP11B1) lies close to CYP11B2. We hypothesize that a molecular variant in CYP11B2 is in linkage disequilibrium (LD) with a key quantitative trait in CYP11B1 determining this phenotype. Polymorphisms and inferred haplotypes at CYP11B loci were studied in two independent populations from Europe (n = 100) and South America (n = 99). The latter underwent detailed hormonal studies. LD was estimated by alternative Bayesian methods for inferring the extent of LD when haplotypes at different loci are inferred. Population differences in single nucleotide polymorphisms were modest, indicating the stability of both genes across populations. Using five of nine potentially informative loci at CYP11B sites with allele frequency greater than 0.1, two major contrasting haplotypes, CwtCG and TconvGTA, were found. In both populations the CwtCG haplotype accounted for 44% and the TconvGTA for 32% of subjects. Haplotype distribution did not differ between Europeans and South Americans (chi(2) = 2.81; P = 0.09). In vivo 11 beta-hydroxylase activity, estimated from urinary steroid profiling, was lower in subjects with an increased aldosterone to renin ratio or with the TconvGTA haplotype. These findings indicate that genotypes at the CYP11B locus are in strong LD and that identified haplotypes predict 11 beta-hydroxylase activity.

Prospects and challenges for the conservation of farm animal genomic resources, 2015-2025.

Livestock conservation practice is changing rapidly in light of policy developments, climate change and diversifying market demands. The last decade has seen a step change in technology and analytical approaches available to define, manage and conserve Farm Animal Genomic Resources (FAnGR). However, these rapid changes pose challenges for FAnGR conservation in terms of technological continuity, analytical capacity and integrative methodologies needed to fully exploit new, multidimensional data. The final conference of the ESF Genomic Resources program aimed to address these interdisciplinary problems in an attempt to contribute to the agenda for research and policy development directions during the coming decade. By 2020, according to the Convention on Biodiversity's Aichi Target 13, signatories should ensure that "…the genetic diversity of …farmed and domesticated animals and of wild relatives …is maintained, and strategies have been developed and implemented for minimizing genetic erosion and safeguarding their genetic diversity." However, the real extent of genetic erosion is very difficult to measure using current data. Therefore, this challenging target demands better coverage, understanding and utilization of genomic and environmental data, the development of optimized ways to integrate these data with social and other sciences and policy analysis to enable more flexible, evidence-based models to underpin FAnGR conservation. At the conference, we attempted to identify the most important problems for effective livestock genomic resource conservation during the next decade. Twenty priority questions were identified that could be broadly categorized into challenges related to methodology, analytical approaches, data management and conservation. It should be acknowledged here that while the focus of our meeting was predominantly around genetics, genomics and animal science, many of the practical challenges facing conservation of genomic resources are societal in origin and are predicated on the value (e.g., socio-economic and cultural) of these resources to farmers, rural communities and society as a whole. The overall conclusion is that despite the fact that the livestock sector has been relatively well-organized in the application of genetic methodologies to date, there is still a large gap between the current state-of-the-art in the use of tools to characterize genomic resources and its application to many non-commercial and local breeds, hampering the consistent utilization of genetic and genomic data as indicators of genetic erosion and diversity. The livestock genomic sector therefore needs to make a concerted effort in the coming decade to enable to the democratization of the powerful tools that are now at its disposal, and to ensure that they are applied in the context of breed conservation as well as development.

Alpha-adducin polymorphism, salt sensitivity, nitric oxide excretion, and cardiovascular risk factors in normotensive Hispanics.

BACKGROUND: Genetic and environmental factors determine the blood pressure (BP) response to changes in salt intake. Mutations in the alpha-adducin gene may be associated with hypertension and salt-sensitive hypertension. We investigated whether one alpha-adducin polymorphism, the Gly460Trp (G/T) variant, was associated with salt sensitivity, nitric oxide (NO) production; and cardiovascular risk factors in healthy adult normotensive Venezuelans. METHODS AND RESULTS: Subjects (n = 126) were screened for salt sensitivity. The alpha-Adducin polymorphism was tested in salt-sensitive (SS) and salt-resistant (SR) subjects. The G/T and G/G (wild gene) groups had similar BP levels. The G/T subjects had higher LDL-cholesterol (P =.01) and postload glucose AUC (P =.03) than G/G individuals. Genotype frequencies were not associated with BP or salt sensitivity (G/G, 38.1% SS and 61.9% SR vs G/T, 40.7% SS and 59.3% SR). Shifting from high salt to low salt diet produced comparable reductions in systolic BP and diastolic BP in G/T and G/G groups. The G/G and G/T groups excreted similar amounts of sodium on high and low salt diets. The SR subjects carrying the wild or the mutated gene showed no changes in NO metabolite excretion at different levels of salt intake. In SS subjects, the level of NO metabolite excretion was highly dependent on salt intake. A combination of SS and 460Trp mutation enhanced the sodium-dependent modulation of NO production. CONCLUSIONS: In normotensive Venezuelans, the alpha-adducin G/T polymorphism was not associated with BP, salt sensitivity, or with sodium excretion during sodium loading or restriction. G/T was associated with increased LDL-cholesterol and postload glucose levels. In SS, G/T was associated with greater salt-dependent modulation of NO excretion. However, this larger increase in NO excretion was not associated with a larger decrease in BP.

Role of salt sensitivity, blood pressure, and hyperinsulinemia in determining high upper normal levels of urinary albumin excretion in a healthy adult population.

BACKGROUND: The objective of this study was to investigate the role of blood pressure (BP), salt sensitivity (SS), and the cardiovascular metabolic syndrome in determining the urinary albumin excretion (UAE) in glucose-tolerant, normoalbuminuric (<20 mg/day) healthy adults. METHODS AND RESULTS: We evaluated 177 healthy subjects (age, 38.3 +/- 0.9 years; weight, 75.2 +/- 1.1 kg; body mass index, 28.8 +/- 0.4 kg/m(2); systolic BP, 117 +/- 1 mm Hg; diastolic BP, 77.5 +/- 0.8 mm Hg; UAE, 8.2 +/- 0.3 mg/24 h). Subjects with UAE levels of 15 to 20 mg/day had higher systolic BP, diastolic BP, and pulse pressures than those with UAE levels less than 15 mg/day (P <.0001). Hypertension (HT) and SS were more prevalent in the high normal UAE group (15 to 20 mg/day) than in groups with lower UAE (47% v 8% for HT and 67% v 24% for SS). In normotensives (n = 156), no differences in BP were observed among the different UAE strata; yet, the prevalence of SS was greater in the high (57%) compared to the low normal (17% to 21%) UAE groups. Similar levels of UAE, BP, and similar prevalence of SS were found in men with and without abdominal obesity, despite the fact that obesity was associated with hypertriglyceridemia and hyperinsulinemia. CONCLUSIONS: In healthy normoalbuminuric adults, high normal UAE is associated with SS in normotensives and with SS and higher BP in a mixed population (88% normotensive and 12% hypertensive). Abdominal obesity, hypertriglyceridemia, and hyperinsulinemia were not related to UAE. Therefore, UAE levels of 15 to 20 mg/day should be accepted as microalbuminuria, and these subjects may benefit from early intervention (ie, salt restriction and BP lowering).

Adaptation to climate change--exploring the potential of locally adapted breeds.

The livestock sector and agriculture as a whole face unprecedented challenges to increase production while improving the environment. On the basis of a literature review, the paper first discusses challenges related to climate change, food security and other drivers of change in livestock production. On the basis of a recent discourse in ecology, a framework for assessing livestock species' and breeds' vulnerability to climate change is presented. The second part of the paper draws on an analysis of data on breed qualities obtained from the Food and Agriculture Organization's Domestic Animal Diversity Information System (DAD-IS) to explore the range of adaptation traits present in today's breed diversity. The analysis produced a first mapping of a range of ascribed adaptation traits of national breed populations. It allowed to explore what National Coordinators understand by 'locally adapted' and other terms that describe general adaptation, to better understand the habitat, fodder and temperature range of each species and to shed light on the environments in which targeted search for adaptation traits could focus.

Metabolic syndrome: an all or none or a continuum load of risk?

OBJECTIVE: The aim of this study was to determine if an increasing number of traits of metabolic syndrome was associated with an increased severity of each of the traits. METHODS: A cohort of otherwise healthy 387 Latin-American subjects was evaluated for traits of metabolic syndrome according to National Cholesterol Education Program Adult Treatment Panel III (NECP ATP III) guidelines. Waist cricumference and triglyceride, high-density lipoprotein cholesterol (HDL-C), and blood pressure (BP) levels were measured. Glucose and insulin levels were obtained after 75 g of oral glucose. RESULTS: The prevalence of subjects with no traits and 1, 2, 3, and 4-5 traits was 10.1%, 27.1%, 36.7%, 20.9%, and 5.1%, respectively. Low HDL-C accounted for 55.2% and larger waist circumference for 30.5% of all cases with one trait. High BP and high glucose contributed mainly as the 4th or 5th trait. Higher values for obesity, abdominal obesity, dyslipidemia, BP, hyperglycemia, and hyperinsulinemia were observed as the number of traits increased from 0 to 4-5 traits. More traits meant more severe traits, even after adjusting by age. Subjects with metabolic syndrome but with 4-5 traits had a much higher risk load than those with 3 traits, due to more traits and more severe traits. CONCLUSIONS: We found that with an increasing number of traits of the metabolic syndrome that the severity of each trait increased. A gradual increase in risk load defined by trait clustering and severity was observed when moving from no traits to fully blown metabolic syndrome. Such a continuum of risk was also observed among subjects with metabolic syndrome, implying that subjects diagnosed with the syndrome may be at quite different risk load.

Impact of traits of metabolic syndrome on ß-cell function and insulin resistance in normal fasting, normal glucose tolerant subjects.

OBJECTIVE: Metabolic syndrome, impaired fasting glucose (IFG), and impaired glucose tolerance (IGT) predict risk for type 2 diabetes mellitus (T2DM). To determine if increased risk preceded development of these abnormalities, ß-cell function and insulin resistance were assessed in euglycemic subjects with and without traits of metabolic syndrome. METHODS: A total of 562 apparently healthy Latin-American subjects were screened for metabolic syndrome [National Education Cholesterol Program Adult Treatment Panel III (NECP ATP III)]. Early pancreatic insulin response ΔInsulin(0-30)/ΔGlucose(0-30), Matsuda index, disposition index (DI), and homeostasis model assessment of insulin resistance (HOMA-IR) ratio were obtained from oral glucose tolerance testing (0-180 min). RESULTS: ΔI(0-30)/ΔG(0-30), Matsuda index, DI, and HOMA-IR deteriorated in direct proportion with number of traits of metabolic syndrome, and with increases in glucose levels within the euglycemic range. DI was the most sensitive index. In subjects with 1, 2, 3, and 4-5 traits, DI was 21.4%, 40%, 57%, and 76% lower, respectively, than in subjects with no traits. As a single trait, abdominal obesity was associated with insulin resistance, whereas, low high-density lipoprotein cholesterol (HDL-C), alone or combined with high triglycerides, was not associated with insulin resistance or ß-cell dysfunction. Combined impairments in ß-cell function and insulin sensitivity were responsible for the increases in fasting and 2-h plasma glucose concentrations within the euglycemic range. CONCLUSIONS: Impaired ß-cell function and increased insulin resistance are present much before development of metabolic syndrome, IFG, or IGT. ß-Cell function and insulin sensitivity worsen in direct proportion with number of traits of metabolic syndrome and increases in glucose levels. Compared to abdominal obesity, low HDL-C±high triglycerides may bear a lesser weight in predicting risk of T2DM.

One-hour postload plasma glucose levels, a predictor of additional risk for diabetes: prevalence, mechanisms, and associated cardiovascular and metabolic risk factors in Hispanics.

OBJECTIVE: The aim of this study was to determine the prevalence of and the mechanisms by which elevated glucose concentrations at 1-h after a glucose load, conferred increased risk for type 2 diabetes mellitus (T2DM). The study was conducted in subjects with glucose abnormalities (impaired fasting glucose [IFG], and impaired glucose tolerance [IGT]), as well as in normal fasting-normal tolerant subjects (NFG-NGT). METHOD: One-hour plasma glucose concentrations were measured as part of 0- to 180-min oral glucose tolerance test (OGTT) performed in an unselected sample of 490 Latino-Hispanics. A cutoff of 154 mg/dL at 1-h during the OGTT was employed, because higher glucose levels define subjects at increased risk for T2DM. Surrogate markers of insulin sensitivity and release, and glucose and insulin time courses were measured. Obesity, cardiovascular risk factors, and presence of metabolic syndrome were also assessed. RESULTS: One-hour plasma glucose concentrations above the cutoff (≥ 155 mg/dL) were found in 8.3% of NFG-NGT, 43% of IFG, 65% of IGT, and in 90% of IFG + IGT, and were associated with greater postload hyperglycemia (AUCG) and hyperinsulinemia (AUCI), and with reductions in indices of beta-cell function (Delta I 0-30/Delta G 0-30 and Delta I 0-180/Delta G 0-180), insulin sensitivity [Matsuda index, homeostasis model assessment of insulin resistance (HOMA-IR)], and disposition index (Delta 0-30/Delta 0-30 G ÷ HOMA-I), markers of increased risk of T2DM. In addition, those with ≥ 155 mg/dL were older, more obese, had higher blood pressure, and higher prevalence of metabolic syndrome. These clinical and metabolic changes were characteristic of subjects with 1-h plasma glucose concentrations ≥ 155 mg/dL, irrespectively of whether they were classified as NFG-NGT, IFG, or IGT. CONCLUSIONS: One-hour postload plasma glucose levels ≥ 155 mg/dL identified a subgroup of subjects, which by current guidelines are classified as NFG-NGT, IFG, or IGT, but that are at a higher risk that their average group risk. Recognition and management of these subjects may reduce incidence of diabetes and cardiovascular events.

Ondansetron and metformin-induced gastrointestinal side effects.

Treatment with metformin is associated with a high incidence of gastrointestinal side effects of unknown mechanism. Metformin is a biguanide derivative, which resembles 5-HT3-receptor agonists in its structure. Activation of 5-HT3 receptors is known to induce nausea, vomiting, and diarrhea. In this study, we investigated if the gastrointestinal side effects produced by metformin were antagonized by ondansetron, a selective antagonist of 5-HT3 receptors. Patients experiencing gastrointestinal side effects were randomized to ondansetron (4 mg bid p.o.) or placebo while maintained on metformin (double-blind, parallel-group design). If side effects persisted or worsened, metformin was discontinued and the patient considered a therapeutic failure. Of the 98 subjects treated with metformin, 22 developed side effects to match the study entry criteria. Diarrhea was the most frequent side effect. Subjects were randomized to ondansetron (10/2 F/M, 42.8 +/- 2.3 years, 28.6 +/- 1.1 kg/m2, 2585 +/- 35 mg/d metformin) or placebo (9/1 F/M, 43 +/- 4.3 years, 29.7 +/- 1.8 kg/m2, 2715 +/- 71 mg/d metformin). Ondansetron showed no efficacy against metformin-induced side effects. A comparable number of therapeutic failures were observed in ondansetron (8/12; 66%) and placebo-treated subjects (5/10; 50%) (P<0.1). Mean nausea scores (numeric analog scale) before and during treatment with ondansetron were 6.3 +/- 1 and 6.9 +/- 1 cm, respectively. Nausea scores averaged 7.3 +/- 1.5 and 5.9 +/- 1.5 cm, before and during treatment with placebo (P>0.1). In conclusion, 5-HT3 receptors do not seem to play a role in metformin-induced gastrointestinal side effects.

Lesion of caudate-putamen interneurons with kainic acid alters dopamine and serotonin metabolism in the olfactory tubercle of the rat.

1. The existence of functional interrelationships between dorsal and ventral regions of the rat striatum was investigated. Kainic acid (KA) was employed to induce neuronal lesions in the more dorsal striatum, the caudate-putamen (CP). Only one CP (one side) received KA. KA-induced neurotoxicity at the site of injection (CP) was evidenced by reductions in choline-acetyltransferase activity and in GABA levels, and by increases in the ratios metabolite/monoamine for dopamine (DA) and serotonin (5-HT). 2. In addition to the well-known local effects, direct stereotaxic injection of KA into the CP produced distant effects in the ipsilateral olfactory tubercle (OT). A dose-dependent increase in the levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA) and decreases in DA and 5-HT concentrations were observed in the OT ipsilateral to the CP injected with KA. With 1, 2, 3, and 4 microg of KA, the ratio DOPAC+HVA/DA in the OT was 30, 79, 140, and 173% higher, respectively, than control levels. With 2, 3, and 4 microg of KA, the levels of 5-HIAA were approximately 30, 60, and 120% higher than control values, and the changes in 5-HIAA were associated with significant reductions in 5-HT concentrations. 3. Our results suggest that the dorsal part of the striatum exerts important regulatory functions over the most ventral striatal region, the OT. Destruction of CP interneurons by KA leads to disinhibition of DA and 5-HT activities to the OT. The functional interactions between dorsal and ventral striatal regions may play a role in the integration of fundamental life-preserving, motivational, and goal-directed olfactory motor behaviors of rodents.