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Objective The activity of brown adipose tissue is sensitive to changes in ambient temperature. A lower exposure to cold could result in an increased risk of developing diabetes at population level, although this factor has not yet been sufficiently studied. Design We studied 5072 subjects, participants in a national, cross-sectional population-based study representative of the Spanish adult population (Di@bet.es study). All subjects underwent a clinical, demographic and lifestyle survey, a physical examination and blood sampling (75 g oral glucose tolerance test). Insulin resistance was estimated with the homeostasis model assessment (HOMA-IR). The mean annual temperature (°C) in each individual municipality was collected from the Spanish National Meteorology Agency. Results Linear regression analysis showed a significant positive association between mean annual temperature and fasting plasma glucose (β: 0.087, P < 0.001), 2 h plasma glucose (β: 0.049, P = 0.008) and HOMA-IR (β: 0.046, P = 0.008) in multivariate adjusted models. Logistic regression analyses controlled by multiple socio-demographic variables, lifestyle, adiposity (BMI) and geographical elevation showed increasing odds ratios for prediabetes (WHO 1999), ORs 1, 1.26 (0.95-1.66), 1.08 (0.81-1.44) and 1.37 (1.01-1.85) P for trend = 0.086, diabetes (WHO 1999) ORs 1, 1.05 (0.79-1.39), 1.20 (0.91-1.59) and 1.39 (1.02-1.90) P = 0.037, and insulin resistance (HOMA-IR ≥75th percentile of the non-diabetic population): ORs 1, 1.03 (0.82-1.30), 1.22 (0.96-1.55), 1.26 (0.98-1.63) (P for trend = 0.046) as the mean annual temperature (into quartiles) rose. Conclusions Our study reports an association between ambient temperature and the prevalence of dysglycemia and insulin resistance in Spanish adults, consistent with the hypothesis that a lower exposure to cold could be associated with a higher risk of metabolic derangements.

Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci., (© 2016 by the American Diabetes Association.)

The dyslipidemia associated with type 2 diabetes mellitus (T2DM) is an important risk factor for atherosclerotic cardiovascular disease. However, until now little attention has been paid to the role that the intestine might have. The aim of this research was to determine the relation between insulin resistance and intestinal de novo lipogenesis/lipoprotein synthesis in morbidly obese subjects and to study the effect of insulin on these processes. Jejunal mRNA expression of the different genes involved in the intestinal de novo lipogenesis/lipoprotein synthesis was analyzed in three groups of morbidly obese subjects: Group 1 with low insulin resistance (MO-low-IR), group 2 with high insulin resistance (MO-high-IR), and group 3 with T2DM and treatment with metformin (MO-metf-T2DM). In addition, intestinal epithelial cells (IECs) from MO-low-IR were incubated with different doses of insulin/glucose. In Group 2 (MO-high-IR), the jejunal mRNA expression levels of apo A-IV, ATP-citrate lyase (ACLY), pyruvate dehydrogenase (lipoamide) beta (PDHB), and sterol regulatory element-binding protein-1c (SREBP-1c) were significantly higher and acetyl-CoA carboxylase alpha (ACC1) and fatty-acid synthase lower than in Group 1 (MO-low-IR). In Group 3 (MO-metf-T2DM), only the ACLY and PDHB mRNA expressions were significantly higher than in Group 1 (MO-low-IR). The mRNA expression of most of the genes studied was significantly linked to insulin and glucose levels. The incubation of IEC with different doses of insulin and glucose produced a higher expression of diacylglycerol acyltransferase 2, microsomal triglyceride transfer protein, apo A-IV, SREBP-1c, and ACC1 when both, glucose and insulin, were at a high concentration. However, with only high insulin levels, there were higher apo A-IV, PDHB and SREBP-1c expressions, and a lower ACLY expression. In conclusion, the jejunum of MO-high-IR has a decreased mRNA expression of genes involved in de novo fatty-acid synthesis and an increase of genes involved in acetyl-CoA and lipoprotein synthesis. This effect is attenuated by metformin. In addition, the expression of most of the genes studied was found to be regulated by insulin.

The aim of the study was to analyze the association between aging and insulin resistance estimated by the homeostasis model assessment of insulin resistance (HOMA-IR). This work involved two studies: (1) the Di@bet.es study is a cross-sectional study including 4,948 subjects, comprising a representative sample of the adult Spanish population; (2) the Pizarra study is a population-based cohort study undertaken in Pizarra (Spain), in which 1,051 subjects were evaluated at baseline and 714 completed the 6-year follow-up study. Study variables included a clinical and demographic structured survey, a lifestyle survey, a physical examination, and an oral glucose tolerance test in subjects without diabetes. In the Di@bet.es study overall, an increase occurred in blood glucose until the age of 50, after which it remained stable (data adjusted for gender, body mass index, abnormal glucose regulation [AGR]). The HOMA-IR increased significantly with age (p = 0.01), due to a higher prevalence of obesity (p < 0.0001) and AGR (p < 0.001). In non-obese subjects without AGR, HOMA-IR values were not modified with age (p = 0.30), but they were with body mass index (p < 0.001). In the Pizarra study, the HOMA-IR was significantly lower after 6-year follow-up in the whole study population. Subjects with a HOMA-IR level higher than the 75th percentile at baseline were more likely to develop diabetes (OR 2.2, 95 % CI 1.2-3.9; p = 0.007) than subjects with a lower HOMA-IR. We concluded that age per se did not increase HOMA-IR levels, changes that might be related to higher rates of obesity and AGR in older subjects. The HOMA-IR was associated with an increased risk of developing type 2 diabetes 6 years later.

Background: Although high-sensitivity C-reactive protein (hs-CRP) is currently used as a risk marker of cardiovascular disease, it has been suggested that genetic, clinical, biochemical or environmental factors could modify hs-CRP levels. The aim of this study was to investigate sources of interindividual hs-CRP variability in the Spanish population., Materials and Methods: A representative sample of the Spanish population within the di@bet.es study was used. Study variables included a clinical and demographic structured survey, a lifestyle survey, a physical examination, plasmatic hs-CRP and other biochemical parameters., Results: Median and interquartile range of plasma hs-CRP values were 1·73 ± 2·75 mg/dL. Thirty per cent of the study population had hs-CRP levels above 3 mg/dL and 38% from 1 to 3 mg/dL. Body mass index was the strongest factor associated with moderate and high hs-CRP levels. Age, sex, waist-to-hip ratio, weight increase, plasma lipid levels, glucose metabolism (HOMA-IR and abnormal glucose regulation categories), pharmacological treatment (lipid-lowering agents, psychotropic drugs and levothyroxine), smoking, physical activity, different dietary patterns, quality of life and educational level were all significantly associated with hs-CRP levels. Interactions were observed between variables. These interactions modulated the effect of previously described factors on hs-CRP., Conclusions: Thirty per cent of the Spanish population have hs-CRP levels considered to represent a cardiovascular risk. Different clinical, anthropometric, biochemical and environmental variables modulate hs-CRP levels. In addition, multiple interactions between variables complicate the interpretation of hs-CRP values., (© 2012 The Authors. European Journal of Clinical Investigation © 2012 Stichting European Society for Clinical Investigation Journal Foundation.)

Summary: The main objective was to evaluate the association between SNPs and haplotypes of the FABP1-4 genes and type 2 diabetes, as well as its interaction with fat intake, in one general Spanish population. The association was replicated in a second population in which HOMA index was also evaluated., Methods: 1217 unrelated individuals were selected from a population-based study [Hortega study: 605 women; mean age 54 y; 7.8% with type 2 diabetes]. The replication population included 805 subjects from Segovia, a neighboring region of Spain (446 females; mean age 52 y; 10.3% with type 2 diabetes). DM2 mellitus was defined in a similar way in both studies. Fifteen SNPs previously associated with metabolic traits or with potential influence in the gene expression within the FABP1-4 genes were genotyped with SNPlex and tested. Age, sex and BMI were used as covariates in the logistic regression model., Results: One polymorphism (rs2197076) and two haplotypes of the FABP-1 showed a strong association with the risk of DM2 in the original population. This association was further confirmed in the second population as well as in the pooled sample. None of the other analyzed variants in FABP2, FABP3 and FABP4 genes were associated. There was not a formal interaction between rs2197076 and fat intake. A significant association between the rs2197076 and the haplotypes of the FABP1 and HOMA-IR was also present in the replication population., Conclusions: The study supports the role of common variants of the FABP-1 gene in the development of type 2 diabetes in Caucasians.

Background: Different studies, mostly cross-sectional, have found an association between low levels of thyroid hormones, even within the normal range, and a greater body mass index. The aim of this study was to determine the association between thyroid function and the risk for obesity., Materials and Methods: In this population-based prospective study, measurements were made of anthropometric parameters, thyroid hormone function and urinary iodine in a cohort of the Pizarra Study (n = 937), and repeated 6 years later (n = 784). At the second point, measurements were also made of leptin and adiponectin., Results: Among the persons who were not obese at the start of the study, the odds ratio (OR) of becoming obese for those in the fourth quartile (Q(4)) for free triiodothyronine (FT3) (versus those in Q(1)) was 2·94 (1·46-5·90) (P = 0·005). The OR of becoming obese in persons in Q(4) of FT4 (versus those in Q(1)) was 3·06 (1·23-7·43) (P = 0·01). Those persons in Q(4) of weight gain had a higher FT3 at the 6-year follow-up than those whose weight gain was in Q(1) (P < 0·001). Leptin correlated with thyrotropin (β = 0·58, P = 0·001) and the FT4 (β = -1·12, P = 0·005). Adiponectin correlated with FT3 (r = -0·24, P < 0·001). The urinary iodine correlated negatively with both the BMI (β = -0·08, P = 0·01) and the increase in weight (β = -0·08, P = 0·04)., Conclusions: The changes in the thyroid hormones could be the consequence, rather than the cause, of the increase in weight. The same pathophysiological mechanisms that induce obesity might also be modifying the thyroid hormone pattern., (© 2011 The Authors. European Journal of Clinical Investigation © 2011 Stichting European Society for Clinical Investigation Journal Foundation.)

Animal studies have revealed the association between stearoyl-CoA desaturase 1 (SCD1) and obesity and insulin resistance. However, only a few studies have been undertaken in humans. We studied SCD1 in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) from morbidly obese patients and their association with insulin resistance, sterol regulatory element binding protein-1 (SREBP-1) and ATPase p97, proteins involved in SCD1 synthesis and degradation. The insulin resistance was calculated in 40 morbidly obese patients and 11 overweight controls. Measurements were made of VAT and SAT SCD1, SREBP-1 and ATPase p97 mRNA expression and protein levels. VAT and SAT SCD1 mRNA expression levels in the morbidly obese patients were significantly lower than in the controls (P = 0.006), whereas SCD1 protein levels were significantly higher (P < 0.001). In the morbidly obese patients, the VAT SCD1 protein levels were decreased in patients with higher insulin resistance (P = 0.007). However, SAT SCD1 protein levels were increased in morbidly obese patients with higher insulin resistance (P < 0.05). Multiple linear regressions in the morbidly obese patients showed that the variable associated with the SCD1 protein levels in VAT was insulin resistance, and the variables associated with SCD1 protein levels in SAT were body mass index (BMI) and ATPase p97. In conclusion, these data suggest that the regulation of SCD1 is altered in individuals with morbid obesity and that the SCD1 protein has a different regulation in the two adipose tissues, as well as being closely linked to the degree of insulin resistance.

Background: The elongase of long chain fatty acids family 6 (ELOVL6) is an enzyme that specifically catalyzes the elongation of saturated and monounsaturated fatty acids with 12, 14 and 16 carbons. ELOVL6 is expressed in lipogenic tissues and it is regulated by sterol regulatory element binding protein 1 (SREBP-1)., Objective: We investigated whether ELOVL6 genetic variation is associated with insulin sensitivity in a population from southern Spain., Design: We undertook a prospective, population-based study collecting phenotypic, metabolic, nutritional and genetic information. Measurements were made of weight and height and the body mass index (BMI) was calculated. Insulin resistance was measured by homeostasis model assessment. The type of dietary fat was assessed from samples of cooking oil taken from the participants' kitchens and analyzed by gas chromatography. Five SNPs of the ELOVL6 gene were analyzed by SNPlex., Results: Carriers of the minor alleles of the SNPs rs9997926 and rs6824447 had a lower risk of having high HOMA&#95;IR, whereas carriers of the minor allele rs17041272 had a higher risk of being insulin resistant. An interaction was detected between the rs6824447 polymorphism and the intake of oil in relation with insulin resistance, such that carriers of this minor allele who consumed sunflower oil had lower HOMA&#95;IR than those who did not have this allele (P = 0.001)., Conclusions: Genetic variations in the ELOVL6 gene were associated with insulin sensitivity in this population-based study.

Background: The intestinal fatty acid-binding protein (FABP2) is involved in the intracellular transport and metabolism of fatty acids and may affect insulin sensitivity and glucose metabolism., Objective: The objective was to study the effect of interaction between the Ala54Thr polymorphism of the FABP2 gene (FABP2) and the type of dietary cooking oil used on peripheral insulin sensitivity in a population from southern Spain., Design: The study was cross-sectional. Anthropometric measurements were obtained for 1226 persons aged 18-65 y selected randomly from the municipal census of Pizarra, Spain. An oral-glucose-tolerance test was given to 1020 of these persons. Insulin resistance was measured by homeostasis model assessment. Samples of the cooking oil being used were taken from the kitchens of a random subset of 538 persons., Results: Persons who consumed sunflower oil and who also had the Thr54 variant had higher insulin resistance than did those who consumed olive oil (P = 0.01). We detected an interaction between the Ala54Thr polymorphism and the type of oil consumed that accounted for the variance in insulin resistance (P = 0.02)., Conclusions: The effect of dietary fatty acids on the populational pattern of insulin resistance is not independent of the Ala54Thr polymorphism of FABP2. An interaction existed between this polymorphism and the intake of dietary fats in a population with a high intake of monounsaturated fatty acids.

Activation of the PPAR gamma 2 gene (PPARG2) improves the action of insulin and its lipid metabolism. We examined the association between Pro12Ala polymorphism of PPARG2, type 2 diabetes mellitus (DM2), and peripheral insulin sensitivity in a population with a high intake of oleic acid. A cross-sectional, population-based study was undertaken in Pizarra, a small town in the province of Malaga in southern Spain. A total of 538 subjects, aged 18-65 y, were selected randomly from the municipal census. All subjects underwent a clinical, anthropometrical, and biochemical evaluation, including an oral glucose tolerance test and Pro12Ala polymorphism of PPARG2. Insulin resistance was measured by homeostasis model assessment. Those subjects with the Ala-12 allele had an odds ratio for impaired fasting glucose of 0.55, for impaired glucose tolerance of 0.59, and for DM2 of 0.30. The intake of monounsaturated fatty acids (MUFA) contributed to the variance of the homeostasis model assessment insulin resistance index (HOMA IR) (P = 0.04), with a 2-way interaction between the Ala-12 allele of PPARG2 and the intake of MUFA (P = 0.005). The results suggest the existence of an interaction between Pro12Ala polymorphism of PPARG2 and dietary MUFA, such that obese people with the Ala-12 allele have higher HOMA IR values, especially if their intake of MUFA is low.

Objective The effects of C-peptide on adipose tissue, an organ involved in the development of obesity and insulin resistance, are not yet well known. The aim of this study was to determine whether C-peptide could be involved in the regulation of the adipocytokine synthesis in human visceral adipose tissue. Methods The association between C-peptide and different serum adipocytokines, with an intravenous glucose tolerance test (IVGTT), and in an in vitro study in subjects without obesity and in subjects with morbid obesity were analyzed. Results In different multiple regression analysis models, C-peptide and C-peptide increase above basal levels during total IVGTT and between 0 and 10 min were associated positively with leptin and negatively with visfatin. Rhodamine-labeled C-peptide binds to human adipocytes, and this binding was blocked with excess of unlabeled C-peptide. Exposure of human visceral explants and adipocytes from subjects with morbid obesity to C-peptide at 1 and 10 nM induced a significant increase in leptin and a decrease in visfatin secretion. In subjects without obesity, these C-peptide effects were found mainly at 10 nM. These effects can be inhibited by phosphatidylinositol 3-kinase (PI3K) or protein kinase B (PKB) inhibitors. Conclusions C-peptide may be involved in the regulation of leptin and visfatin secretion, molecules intimately involved in energy homeostasis processes, through PI3K or PKB pathways. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2012; 42 (1): 79-85 Abstract Aim To evaluate the association between serum levels of testosterone, sex hormone-binding globulin (SHBG) and calculated bioavailable testosterone (bioT), and the risk of type 2 diabetes mellitus (T2D) in a prospective cohort from southern Spain (Pizarra study). Research design and methods The study was performed in the Pizarra Cohort Study, a prospective study started in 1995 with a follow-up of 11 years. Anthropometric and metabolic variables were measured at baseline and at 6 and 11 years of follow-up. Total testosterone (TT), SHBG and calculated bioT were determined at the 6-year follow-up. Results The levels of TT and bioT in men were negatively associated with the risk of obesity, T2D and the metabolic syndrome. In women, the levels of TT and bioT were associated positively with the risk of insulin resistance. The levels of SHBG were associated negatively with the risk of T2D, obesity and insulin resistance in both men and women. For all groups, the association was higher at the 11-year follow-up. Conclusions Low levels of testosterone and SHBG increase the risk of T2D in men, and high levels of testosterone increase the risk of insulin resistance in women. The association between TT levels and the risk of T2D is not completely independent of other variables, such as exposure time, adiposity, insulin resistance or SHBG levels. This study also shows that the different responses between men and women are probably because of the protective effect of SHBG, levels of which are higher in women than in men. [ABSTRACT FROM AUTHOR]

Objective Numerous genes have been associated with the risk for type 2 diabetes mellitus (DM2). In an attempt to understand how specific variants of different genes interact and intervene in the molecular and physiological mechanisms of disorders such as diabetes or insulin resistance, the search for gene–gene interactions is constantly growing. We searched for a possible interaction between two polymorphisms (Trp64Arg of ADRB3 gene and –75G/A of APOA1gene) and the risk for DM2 in a population from southern Spain. Design and methods A cross-sectional study in southern Spain of 1020 people, aged 18–65 years. All persons underwent a clinical, anthropometrical and biochemical evaluation, including an oral glucose tolerance test (OGTT). Insulin resistance was measured by homeostasis model of assessment (HOMA). The polymorphisms –75G/A of APOA1 and Trp64Arg of ADRB3 were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and real-time PCR, respectively. Results The genotype frequencies of the –75G/A polymorphism of the APOA1 gene were 62·7% GG, 25·7% GA and 11·6% AA, whereas for the Trp64Arg polymorphism of the ADRB3 gene, they were 87·5% Trp/Trp, 11·7% Trp/Arg and 0·8% Arg/Arg. Subjects with both gene variants had a greater odds ratio (OR) of having DM2 [OR = 5·5; 95% confidence interval (CI) = 1·2–23·5] than persons with one or none of the variants, after adjusting for age, sex, body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA-IR). Conclusions Joint association of allele –75A ( APOA1) and allele Arg64 ( ADRB3) increase the risk of DM2 in a population from southern Spain. [ABSTRACT FROM AUTHOR]