ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

Risk factors associated with retinal vein occlusion.

AIMS: Retinal vein occlusion (RVO) is the most frequent retinal vascular disease after diabetic retinopathy in which arterial risk factors are much more relevant than venous factors. The objective was to evaluate the role of risk factors in the development of the first episode of RVO. SUBJECTS AND METHODS: One hundred patients with RVO [mean age 56 years, 42% females and mean body mass index (BMI) 27.5 kg/m(2)] were recruited consecutively from the outpatient clinic of a tertiary hospital in Valencia (Spain). All subjects underwent clinical assessment including anthropometric and blood pressure measurements and laboratory test including homocysteine, antiphospholipid antibodies (aPLAs) and thrombophilia studies. In half of the subjects, a carotid ultrasonography was performed. Three control populations matched by age, sex and BMI from different population-based studies were used to compare the levels and prevalence of arterial risk factors. One cohort of young patients with venous thromboembolic disease was used to compare the venous risk factors. RESULTS: Blood pressure levels and the prevalence of hypertension were significantly higher in the RVO population when compared with those for the general populations. There was also a large proportion of undiagnosed hypertension within the RVO group. Moreover, carotid evaluation revealed that a large proportion of patients with RVO had evidence of subclinical organ damage. In addition, homocysteine levels and prevalence of aPLAs were similar to the results obtained in our cohort of venous thromboembolic disease. CONCLUSIONS: The results indicate that hypertension is the key factor in the development of RVO, and that RVO can be the first manifestation of an undiagnosed hypertension. Furthermore, the majority of these patients had evidence of atherosclerotic disease. Among the venous factors, a thrombophilia study does not seem to be useful and only the prevalence of hyperhomocysteinaemia and aPLAs is higher than in the general population.

Thyroid hormone receptor alpha gene variants increase the risk of developing obesity and show gene-diet interactions.

OBJECTIVE: Thyroid hormone receptor-beta resistance has been associated with metabolic traits. THRA gene sequencing of an obese woman (index case) who presented as empirical thyroid hormone receptor-α (THRA) resistance, disclosed a polymorphism (rs12939700) in a critical region involved in TRα alternative processing. DESIGN AND SUBJECTS: THRA gene variants were evaluated in three independent europid populations (i) in two population cohorts at baseline (n=3417 and n=2265), 6 years later (n=2139) and (ii) in 4734 high cardiovascular risk subjects (HCVR, PREDIMED trial). RESULTS: The minor allele of the index case polymorphism (rs12939700), despite having a very low frequency (4%), was significantly associated with higher body mass index (BMI) (P=0.042) in HCVR subjects. A more frequent THRA polymorphism (rs1568400) was associated with higher BMI in subjects from the population (P=0.00008 and P=0.05) after adjusting for several confounders. Rs1568400 was also strongly associated with fasting triglycerides (P dominant=3.99 × 10(-5)). In the same sample, 6 years later, age and sex-adjusted risk of developing obesity was significantly increased in GG homozygotes (odds ratio 2.93 (95% confidence interval, 1.05-6.95)). In contrast, no association between rs1568400 and BMI was observed in HCVR subjects, in whom obesity was highly prevalent. This might be explained by the presence of an interaction (P <0.001) among the rs1568400 variant, BMI and saturated fat intake. Only when saturated fat intake was high (>24.5 g d(-1)), GG carriers showed a significantly higher BMI than A carriers after controlling for energy intake and physical activity. CONCLUSIONS: THRA gene polymorphisms are associated with obesity development. This is a novel observation linking the THRA locus to metabolic phenotypes.

Mediterranean diet adherence in individuals with prediabetes and unknown diabetes: the Di@bet.es Study.

BACKGROUND AND AIMS: Mediterranean diet (MedDiet) is causally related to diabetes and is a dietary pattern recommended to individuals with diabetes. We investigated MedDiet adherence in individuals with prediabetes and unknown (PREDM/UKDM) or known diabetes (KDM) compared to those with normal glucose metabolism (NORMAL). METHODS: This was a national, population-based, cross-sectional, cluster-sampling study. MedDiet adherence was scored (MedScore, mean ± SD 24 ± 5) using a qualitative food frequency questionnaire. Logistic regression was used to examine the association between MedScore and PREDM/UKDM or KDM versus control subjects. RESULTS: We evaluated 5,076 individuals. Mean age was 50 years, 57% were female, 826 (582/244) were PREDM/UKDM, 478 were KDM and 3,772 were NORMAL. Mean age increased across MedScore tertiles (46, 51 and 56 years, p < 0.0001). Higher age-adjusted adherence to MedDiet (5-unit increment in the MedScore) was associated with lower and nondifferent odds (OR, 95% CI) of prevalent PREDM/UKDM (0.88, 0.81-0.96, p = 0.001) and KDM (0.97, 0.87-1.07, p = 0.279), respectively, compared to individuals in the NORMAL group. CONCLUSIONS: In a representative sample of the whole Spanish population, MedDiet adherence is independently associated with PREDM/UKDM. Therapeutic intervention may be, in part, responsible for the lack of differences in adherence observed between the KDM and NORMAL groups. However, reverse causation bias cannot be ruled out in cross-sectional studies.

Prevalence of diabetes mellitus and impaired glucose regulation in Spain: the Di@bet.es Study.

AIMS/HYPOTHESIS: The Di@bet.es Study is the first national study in Spain to examine the prevalence of diabetes and impaired glucose regulation. METHODS: A population-based, cross-sectional, cluster sampling study was carried out, with target population being the entire Spanish population. Five thousand and seventy-two participants in 100 clusters (health centres or the equivalent in each region) were randomly selected with a probability proportional to population size. Participation rate was 55.8%. Study variables were a clinical and demographic structured survey, lifestyle survey, physical examination (weight, height, BMI, waist and hip circumference, blood pressure) and OGTT (75 g). RESULTS: Almost 30% of the study population had some carbohydrate disturbance. The overall prevalence of diabetes mellitus adjusted for age and sex was 13.8% (95% CI 12.8, 14.7%), of which about half had unknown diabetes: 6.0% (95% CI 5.4, 6.7%). The age- and sex-adjusted prevalence rates of isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined IFG-IGT were 3.4% (95% CI 2.9, 4.0%), 9.2% (95% CI 8.2, 10.2%) and 2.2% (95% CI 1.7, 2.7%), respectively. The prevalence of diabetes and impaired glucose regulation increased significantly with age (p < 0.0001), and was higher in men than in women (p < 0.001). CONCLUSIONS/INTERPRETATION: The Di@bet.es Study shows, for the first time, the prevalence rates of diabetes and impaired glucose regulation in a representative sample of the Spanish population.

Associations between surrogate measures of insulin resistance and waist circumference, cardiovascular risk and the metabolic syndrome across Hispanic and non-Hispanic white populations.

AIMS: We evaluated the relations between surrogate indices of insulin resistance and waist circumference, metabolic syndrome and coronary heart disease risk across Hispanic and non-Hispanic white populations. METHODS: The study was a cross-sectional analysis of participants without diabetes in the San Antonio Heart Study, Mexico City Diabetes Study and Spanish Insulin Resistance Study. We evaluated commonly used indices of insulin resistance, including homeostasis model assessment, McAuley's index, Gutt's insulin sensitivity index, Avignon's insulin sensitivity index and the Stumvoll index with and without demographics, the modified Matsuda index and the product of the triglycerides and glucose index. The metabolic syndrome was defined by American Heart Association/National Heart, Lung, and Blood Institute criteria and coronary heart disease risk by Framingham risk scores. RESULTS: The Stumvoll index with demographics and the Avignon's insulin sensitivity index had the strongest correlations with waist circumference across populations. The triglycerides and glucose and McAuley's indices had the most robust correlations with Framingham risk score. The triglycerides and glucose index had the greatest ability to detect individuals with the metabolic syndrome and ≥ 10% coronary heart disease risk. Some indices display significant variability in the strength of the relationship with adiposity and coronary heart disease risk across populations. CONCLUSIONS: There are significant differences between insulin resistance indices regarding the ability to detect the metabolic syndrome and coronary heart disease risk across populations. Studies may need to consider the index of insulin resistance that best suits the objectives.

Hypertriglyceridemic waist: an alternative to the metabolic syndrome? Results of the IMAP Study (multidisciplinary intervention in primary care).

AIM: To study the prevalence of hypertriglyceridemic waist (HTGW) in an urban adult Spanish population and its association with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). METHODS: We undertook a cross-sectional analysis in a random sample of 2270 individuals (18-80 years of age). All participants provided a clinical history and underwent a physical examination. Blood and urine analyses were conducted. HTGW was diagnosed using anthropometric criteria for the European population (waist circumference: for men, ≥ 94 cm; for women, ≥ 80 cm) and fasting plasma triglycerides (TGs) ≥ 1.71 mmol l(-1) (≥ 150 mg per 100 ml). RESULTS: The prevalence of HTGW was 14.5% (men: 18.2%, women: 10.8%) and was significantly greater in men <59 years (P<0.001). HTGW was associated with older individuals, a low educational level and, in men, with a sedentary lifestyle (P<0.001). Subjects with HTGW had higher levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-c) and uric acid, lower levels of high-density lipoprotein-cholesterol, a higher blood pressure, a greater degree of obesity and a higher prevalence of T2DM (20.00 vs 6.4%, P<0.001) (odds ratio (OR) 3.61; 95% confidence interval (95% CI), 2.60-5.01) and CVD (8.5 vs 3.4%, P<0.001) (OR 2.63; 95% CI, 1.66-4.16). The association of HTGW with T2DM and CVD disappeared after adjusting for age. The degree of concordance between HTGW and the metabolic syndrome (MS) was moderate, with both the Adult Treatment Panel III Report (ATP-III) and the International Diabetes Federation criteria (κ=0.51 and κ=0.58, respectively). Subjects with isolated HTGW as compared with those with isolated MS (ATP-III) were younger, had greater levels of total cholesterol, LDL-c and TGs and a lower prevalence of obesity, high blood pressure and dysglycemia. CONCLUSION: HTGW is a phenotype of cardiometabolic risk prevalent in the adult population in our environment. HTGW may be an alternative to MS to detect the population at risk for T2DM and CVD, especially in young individuals who do not fulfill the criteria for MS.

HbA(1c) in adults without known diabetes from southern Europe. Impact of the new diagnostic criteria in clinical practice.

AIMS: To analyse the differences in the prevalence of diabetes and dysglycaemia using fasting plasma glucose and HbA(1c) criteria. METHODS: Analytical cross-sectional study undertaken in a random sample of 2144 individuals (age 18-80 years) without known diabetes from the primary care setting in Malaga (Spain). Dysglycaemia was defined as fasting plasma glucose 5.6-6.9 mmol/l or HbA(1c) 39-46 mmol/mol (5.7-6.4%) and diabetes as fasting plasma glucose ≥ 7.0 mmol/l or HbA(1c)≥ 48 mmol/mol (≥ 6.5%). RESULTS: The proportion of subjects who were normoglycaemic was significantly higher using fasting plasma glucose than HbA(1c) (83.5 vs. 65%) (P < 0.0001). Compared with fasting plasma glucose, HbA(1c) detects more cases of dysglycaemia (32 vs. 14.8%) (P < 0.0001) and diabetes (3 vs. 1.7%) (P < 0.0001). CONCLUSIONS: In our environment, using HbA(1c) for the diagnosis of pre-diabetes and diabetes could increase the target population for preventive and therapeutic measures. Further cost-effectiveness studies are needed before the widespread diagnostic use of HbA(1c) can be recommended.

Identification of a 2244 base pair interstitial deletion within the human ESR1 gene in the Spanish population.

BACKGROUND: The ESR1 AGATA haplotype is composed of five markers located within introns 5 and 6 of the human oestrogen receptor 1 (ESR1) gene. This haplotype has been studied in several male urogenital tract anomalies and male infertility. In one of these studies, a deviation from Hardy-Weinberg equilibrium (DHW) was found for the ESR1 AGATA marker rs3020375 in two groups of healthy controls. In the present study, we investigated whether the observed DHW is caused by structural variants present within the ESR1 gene. PARTICIPANTS: 229 family units achieving pregnancy through assisted reproductive technologies (n = 129) or by natural means (n = 100), 2465 general Spanish population controls and 162 men with idiopathic infertility. MAIN OUTCOME MEASUREMENTS: Segregation analyses of genetic markers in family units and case-control genetic association studies. RESULTS: We identified a new interstitial deletion of 2244 base pairs within intron 6 of the human ESR1 gene as the cause for the observed DHW. This new variant presents a 10% allelic frequency in the general Spanish population and it is associated with idiopathic male infertility (OR = 1.51; p = 0.03). The percentage of infertile couples in which both members carried the ESR1 deletion (10.08%) was also a higher than expected value of 6% (p = 0.03). CONCLUSIONS: We have characterised a novel structural variation in human ESR1 gene. The available data indicate a deleterious action of the ESR1 deletion in both male and couple fertility. The potential effects of this deletion on other oestrogen-related diseases need to be determined.

Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance.

The nucleotide sequence was determined for all 22 exons of the insulin receptor gene from three patients with genetic syndromes associated with extreme insulin resistance. In all three patients, insulin resistance was caused by decreased insulin binding to the cell surface. The patient with leprechaunism (leprechaun/Winnipeg) came from a consanguineous pedigree and was homozygous for a missense mutation substituting arginine for His209 in the alpha-subunit of the insulin receptor. The other two patients were both compound heterozygotes with a nonsense mutation in one allele of the insulin receptor gene, and a missense mutation in the other allele. In the patient with the Rabson-Mendenhall syndrome (patient RM-1), the missense mutation substituted lysine for Asn15 in the alpha-subunit. In the patient with type A extreme insulin resistance (patient A-1), the missense mutation substituted serine for Asn462 in the alpha-subunit. Both nonsense mutations markedly reduced the levels of insulin receptor mRNA transcribed from the alleles with the nonsense mutation as compared to the transcripts from the other allele. The reduction in the level of mRNA would be predicted to greatly reduce the rate at which the truncated receptors would be synthesized. Furthermore, the truncated receptors would be severely impaired in their ability to mediate insulin action.

Insulin-receptor biosynthesis in cultured lymphocytes from an insulin-resistant patient (Rabson-Mendenhall syndrome). Evidence for defect before insertion of receptor into plasma membrane.

In some patients with genetic forms of extreme insulin resistance, there is a marked decrease in the number of insulin receptors on the cell surface. We studied an insulin-resistant patient (RM-1) with the Rabson-Mendenhall syndrome. As judged by insulin-binding studies, Epstein-Barr virus-transformed lymphocytes from patient RM-1 exhibit a 90% decrease in the number of insulin receptors. Similarly, with either lactoperoxidase-catalyzed radioiodination of cell surface receptors or biosynthetic labeling of receptors with [3H]glucosamine, we demonstrated an 80-90% decrease in the number of insulin receptors in cells from patient RM-1. Previous studies have shown that the marked decrease in insulin receptors of the Rabson-Mendenhall patient is not due to accelerated receptor degradation. Therefore, we investigated the possibility that a slow rate of receptor biosynthesis might account for the 90% reduction of insulin receptors in cells from this patient. Insulin-receptor biosynthesis proceeds through a glycoprotein precursor with an apparent Mr of 190,000. It undergoes endopeptidase cleavage and further posttranslational processing to yield the mature 135,000- and 95,000-Mr glycoprotein subunits. We studied the biosynthesis of the 190,000-Mr precursor and mature receptor subunits by a pulse-chase labeling technique with [2-3H]mannose. The time course of insulin-receptor biosynthesis appeared normal in cells from patient RM-1, despite a 10-fold reduction in the number of receptors on the cell surface. Parallel pulse-chase experiments with either [2-3H]mannose or [35S]methionine yielded the same results regardless of which label was employed. Thus, the receptor precursor in the Rabson-Mendenhall patient seems to be synthesized at a normal rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33.

Polymorphic markers within the CTLA4 gene on chromosome 2q33 have been shown to be associated with type 1 diabetes. Therefore, a gene responsible for the disease (IDDM12) most likely lies within a region of <1-2 cM of CTLA4. To define more precisely the IDDM12 interval, we genotyped a multiethnic (U.S. Caucasian, Mexican-American, French, Spanish, Korean, and Chinese) collection of 178 simplex and 350 multiplex families for 10 polymorphic markers within a genomic interval of approximately 300 kb, which contains the candidate genes CTLA4 and CD28. The order of these markers (D2S346, CD28, GGAA19E07, D2S307, D2S72, CTLA4, D2S105, and GATA52A04) was determined by sequence tagged site content mapping of bacterial artificial chromosome (BAC) and yeast artificial chromosome (YAC) clones. The transmission disequilibrium test (TDT) analyses of our data revealed significant association/linkage with three markers within CTLA4 and two immediate flanking markers (D2S72 and D2S105) on each side of CTLA4 but not with more distant markers including the candidate gene CD28. Tsp analyses revealed significant association only with the three polymorphic markers within the CTLA4 gene. The markers linked and associated with type 1 diabetes are contained within a phagemid artificial chromosome clone of 100 kb, suggesting that the IDDM12 locus is either CTLA4 or an unknown gene in very close proximity.

Was the historic contribution of Spain to the Mexican gene pool partially responsible for the higher prevalence of type 2 diabetes in mexican-origin populations? The Spanish Insulin Resistance Study Group, the San Antonio Heart Study, and the Mexico City Diabetes Study.

OBJECTIVE: Mexican-American populations in San Antonio, Texas (SA-MA) and Mexico have a higher prevalence of type 2 diabetes than non-Hispanic whites in San Antonio (SA-NHW). However, the higher prevalence of type 2 diabetes in Mexican-origin populations might be related, in part, not to Native American genetic admixture but to Spanish genetic admixture. RESEARCH DESIGN AND METHODS: Four population-based epidemiological surveys conducted with Mexican-origin and European-origin samples provided data relevant to this question. In all four surveys, type 2 diabetes was defined as fasting plasma glucose > or =7.0 mmol/l or 2-h glucose > or =11.1 mmol/l or use of antidiabetic agents. RESULTS: A comparison of the two Mexican-origin populations showed that the age- and sex-adjusted prevalence of type 2 diabetes was lower in Mexico than in SA-MA (15.1 vs. 17.9%, P = 0.032). Between the two European-origin populations, the prevalence of type 2 diabetes was lower in SA-NHW than in Spain (6.2 vs. 9.1%, P < 0.0001), but differences were attenuated by adjustment for BMI or after stratification by education. In logistic regression analyses, type 2 diabetes was associated with Mexican ethnic origin after adjusting for age, education, BMI, and waist-to-hip ratio. CONCLUSIONS: The prevalence of type 2 diabetes in Spain was intermediate between that in Mexican-origin populations and SA-NHW. Although the higher degree of Native American admixture is a major contributor to the higher rates of type 2 diabetes, we cannot completely rule out a partial contribution of Spanish admixture to diabetes susceptibility among Mexican- origin populations.

Long-term metabolic consequences of switching from protease inhibitors to efavirenz in therapy for human immunodeficiency virus-infected patients with lipoatrophy.

The roles of nucleoside analogues and protease inhibitors (PIs) in the development of metabolic complications and fat-distribution abnormalities associated with highly active antiretroviral therapy (HAART) are not well known. We performed an observational study in which efavirenz was substituted for a PI for 41 patients receiving HAART who had prolonged virus suppression, clinical signs of severe lipoatrophy, hyperlipidemia, and insulin resistance. Clinical follow-up was performed for 1 year. Virus suppression was maintained in most of the patients, and a significant increase in CD4(+) lymphocyte count was observed, but no change in lipid profile or insulin resistance was observed. Abdominal fat content did not change, and subcutaneous fat depletion was even more pronounced >1 year after the switch. We conclude that, for PI-treated patients who present with lipoatrophy, hyperlipidemia, and insulin resistance, substituting efavirenz for PIs can maintain virus suppression and immunologic response to HAART, but it does not improve the lipid profile or resolve insulin resistance or lipoatrophy.

Lack of preferential transmission of diabetic HLA alleles by healthy parents to offspring in Spanish diabetic families.

HLA-DR3 or -DR4 segregation distortion to normal or insulin-dependent (ID) diabetic offspring of 108 Spanish families whose parents were healthy was not observed; however, DR3 or DR4 ID offspring is significantly increased in the present study, since parents were chosen after tracing ID children. These results are discrepant with those found by others in families with diabetic parents in other ethnic groups. These conflicting data could be due to sampling errors or segregation distortion. Thus, ethnic group differences in a genetic (T/t-like) or metabolic mechanism might confer advantages to DR3- or DR4-bearing gametes from ID diabetic parents, but segregation distortion might only affect certain HLA DR3 or DR4 extended haplotypes which are frequent and characteristic for certain ethnic groups (i.e. B8-DR3-BfS-C4AQOB1 and Bw62-DR3-BfS-C4A383 in most caucasians) but not for other haplotypes in other ethnic groups (Spaniards; B18-DR3-BfF1-C4A3BQO and BwX-DR4-BfX-C4AXBX).

Effect of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma-2 gene on adiposity, insulin sensitivity and lipid profile in the Spanish population.

OBJECTIVE: To investigate the role of the Pro12Ala peroxisome proliferator-activated receptor (PPAR) gamma-2 polymorphism in the susceptibility to the insulin resistance syndrome and its metabolic complications in a population-based nationwide multicenter study in Spain. DESIGN: 464 unrelated adults (45.3% men and 54.7% women) aged between 35 and 64 years were randomly chosen from a nationwide population-based survey of obesity and related conditions including insulin resistance and cardiovascular risk factors. METHODS: Anthropometric determinations included: body mass index (BMI), waist-to-hip ratio, sagittal abdominal diameter; biochemical determinations included: fasting plasma glucose concentration and concentration 2 h after an oral glucose tolerance test (OGTT), total cholesterol, high and low density lipoprotein-cholesterol, triglycerides, leptin and insulin. Systolic and diastolic blood pressure were also measured. Genotyping of the PPARgamma-2 Pro12Ala polymorphism was determined by polymerase chain reaction and single strand conformation polymorphism analysis. RESULTS: The Ala12 allele frequency was higher in obese men than in lean men (0.15 vs 0.08, P=0.03). Men carriers of the Ala12 allele had a higher BMI than non-carriers (38.9% vs 21.3%; adjusted odds ratio 2.36, 95% confidence interval 1.10-5.05, P=0.03). However, despite higher BMI obese men carriers of the Ala12 allele had lower sagittal abdominal diameter than Pro12 homozygotes (24.1+/-3.2 vs 26.3+/-2.5 cm, P=0.01). The Ala12 allele was associated with lower total triglycerides levels in the overall population and it was also associated with lower fasting insulin levels and a higher insulin sensitivity by homeostasis model assessment (HOMA) in women. CONCLUSIONS: Our results suggest that the Pro12Ala polymorphism of the PPARgamma-2 gene promotes peripheral deposition of adipose tissue and increased insulin sensitivity for a given BMI. The results in women might be due to their different adipose tissue distribution.

Long survival of diarrhea-associated hepatocarcinoma treated with Adriamycin and indomethacin. A case report.

The existence of tumors producing prostaglandins is well documented in the literature. At present, no case report of a prostaglandin-producing hepatocellular carcinoma has been published, to our knowledge. The authors report a patient with hepatocellular carcinoma associated with diarrhea mediated by prostaglandins, surviving 30 months after receiving treatment with indomethacin and Adriamycin. The authors will discuss the possible role played by indomethacin in the exceptional clinical course of the patient.

hCS regulation during pregnancy.

In order to define the homeostatic mechanisms which affect the secretion of human chorionic somatomammotropin (hCS), we have determinated its plasma levels by a radioimmunoassay method in normal, prediabetic, and chemically diabetic pregnant women in basal conditions and after stimuli. Oral glucose failed to modify hCS plasma levels as also did continuous intravenous glucose infusion. Rapid acute intravenous glucose decreased them, suggesting that only sudden changes in maternal plasma glucose can exert a regulatory effect on hCS secretion. In travenous arginine increased hCS levels, new evidence of the great similarity of structure and function between growth hormone and hCS.

Effect of two new alpha-glucosidase inhibitors in insulin-dependent diabetic patients.

The delay in glucose absorption at the intestinal level obtained with the administration of alpha-glucosidase inhibitors may contribute to an improved metabolic control in diabetic patients. We have examined the effects of two new compounds, BAY m 1099 (short acting) and BAY o 1248 (long acting), on the postprandial glycemic changes, the insulin requirements and the meal-induced hormone responses in nine insulin-dependent diabetics (IDD). The investigation was conducted according to a protocol in which medication and placebo were administered in a double-blind randomized manner. Twelve hours before each experimental day, the patients were connected to the Biostator GCIIS (Ames-Miles) to maintain stabilized normoglycemic levels for the whole period of study. The results showed that: (1) BAY m 1099 decreased the 4-h postprandial glycemic excursions compared to placebo both at dinner and breakfast (P less than 0.05), (2) BAY o 1248 when compared with placebo showed a significant lowering of the peak glycemic levels at breakfast (P less than 0.001) and at lunch (P less than 0.0025), (3) the 2-h and 4-h post-breakfast insulin requirements fell significantly after either drug (P less than 0.02), (4) the plasma levels of contrainsular hormones were not affected by drugs or placebo at any time during the period of study, and (5) no side effects with either drug could be detected. We conclude from our study that both drugs may be useful adjuncts to insulin therapy in insulin-dependent diabetics by reducing postprandial glycemic fluctuations as well as by decreasing insulin requirements with no modification of the meal-induced hormone responses.