Increased Fasting Insulin Research Articles

The increase of fatty acid-binding protein aP2 in overweight and obese children: interactions with dietary fat and impact on measures of subclinical inflammation

In adults, circulating aP2 may link obesity, inflammation and the metabolic syndrome, but there are few data in children. Experimental models support that dietary factors, particularly dietary fat, may be major determinants of phenotype. The aim of this study was to investigate, in normal, overweight and obese children, the relationships among aP2, the metabolic syndrome, inflammation and diet. This was a cross-sectional study conducted in Northern Switzerland. Subjects for this study were 6- to 14-year-old, prepubertal and early pubertal, normal weight, overweight and obese children (n=124). Body mass index (BMI), body fat percent, waist-to-hip ratio, blood pressure, circulating aP2, fasting insulin, C-reactive protein (CRP), plasma lipids and dietary intakes of macro- and micronutrients were determined. Circulating aP2 markedly increased with increasing central and total adiposity, and predicted measures of insulin resistance. Independent of BMI standard deviation scores and puberty, aP2 correlated with intake of the antioxidant vitamins A, C and E as well as circulating concentrations of CRP, leptin and low-density lipoprotein cholesterol. Children with lower aP2 concentrations consuming high-fat diets did not show an increase in fasting insulin or CRP, whereas those with higher aP2 concentrations showed marked increases in these measures with high intakes of fat or saturated fat. Increased central and overall adiposity in children are associated with higher circulating aP2 concentrations. In children with high dietary intakes of total fat and saturated fat, but not those with low intakes, higher aP2 concentrations are associated with measures of insulin resistance and inflammation.

A novel mutation in the human aromatase gene: Insights on the relationship among serum estradiol, longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment

ObjectiveHere we report on a new case of human aromatase deficiency in a man of 26 years of age and present the results of five year follow-up during trandermal estradiol (tE2) substitution, focusing on bone growth and mineralization. The lack of patient's compliance to tE2 treatment, resulting in low but detectable serum estradiol levels, provides helpful information about the physiological estradiol needed in serum to guarantee a complete bone maturation and mineralization. DesignClinical case report study. MethodsGenetic, biochemical and hormonal evaluations and the study of bone health were performed before and during estrogen treatment. ResultsEunuchoid body proportions, unfused epiphyses, tall stature, osteopenia, increase fasting insulin, mild astenozoospermia and a history of right cryptorchidism were present. Baseline serum FSH was slightly above the normal range and estradiol was undetectable. Genetic analysis revealed a pattern of compound heterozygosity due to 23 bp deletion in exon IV and a point mutation in the first nucleotide of intron IX of the CYP19A1 gene, respectively. The closure of epiphyseal cartilage, the normalization of bone BMD and bone turnover markers, and the improvement of insulin levels were reached during tE2 only when serum estradiol raised above 73 pmol/L. Sperm parameters and overweight did not improve with substitutive therapy. ConclusionsThis new case of aromatase deficiency underlines the role of estrogen on skeletal maturation, BMD, metabolic abnormalities and gonadal axis. It provides evidence on the need not only of a continuous estrogen replacement, but also of ensuring adequate estradiol levels in serum in order to ensure a complete bone maturation and mineralization and to prevent the worsening of body skeletal proportions. The comprehension of this physiological aspect has relevant clinical significance especially for the development of new therapeutic strategies useful to treat growth disorders by targeting serum estradiol in men.

Evidence that autonomic mechanisms contribute to the adaptive increase in insulin secretion during dexamethasone-induced insulin resistance in humans

This study examined whether autonomic mechanisms contribute to adaptively increased insulin secretion in insulin-resistant humans, as has been proposed from studies in animals. Insulin secretion was evaluated before and after induction of insulin resistance with or without interruption of neural transmission. Insulin resistance was induced by dexamethasone (15 mg given over 3 days) in nine healthy women (age 67 years, BMI 25.2+/-3.4 kg/m(2), fasting glucose 5.1+/-0.4 mmol/l, fasting insulin 46+/-6 pmol/l). Insulin secretion was evaluated as the insulin response to intravenous arginine (5 g) injected at fasting glucose and after raising glucose to 13 to 15 mmol/l or to >28 mmol/l. Neural transmission across the ganglia was interrupted by infusion of trimethaphan (0.3-0.6 mg kg(-1) min(-1)). As an indication of insulin resistance, dexamethasone increased fasting insulin (to 75+/-8 pmol/l, p<0.001) without significantly affecting fasting glucose. Arginine-induced insulin secretion was increased by dexamethasone at all glucose levels (by 64+/-12% at fasting glucose, by 80+/-19% at 13-15 mmol glucose and by 43+/-12% at >28 mmol glucose; p <0.001 for all). During dexamethasone-induced insulin resistance, trimethaphan reduced the insulin response to arginine at all three glucose levels. The augmentation of the arginine-induced insulin responses by dexamethasone-induced insulin resistance was reduced by trimethaphan by 48+/-6% at fasting glucose, 61+/-8% at 13-15 mmol/l glucose and 62+/-8% at >28 mmol/l glucose (p<0.001 for all). In contrast, trimethaphan did not affect insulin secretion before dexamethasone was given. Autonomic mechanisms contribute to the adaptative increase in insulin secretion in dexamethasone-induced insulin resistance in healthy participants.

Body mass index status is effective in identifying metabolic syndrome components and insulin resistance in Pacific Island teenagers living in New Zealand

Although adults of Pacific ethnicity living in New Zealand have more than double the prevalence of diabetes and cardiovascular disease than the general population, little is known regarding the presence of risk factors for these disorders among young Pacific Islanders. The study aim was to examine relationships between body composition, glucose and lipid metabolism, and components of the metabolic syndrome (MS) in a community sample of Pacific Island (PI) teenagers living in Dunedin. Anthropometry, body composition (dual-energy x-ray absorptiometry), glucose and lipid metabolism, insulin resistance (homeostasis model assessment [HOMA2], McAuley index), and components of MS were assessed in 80 PI teenagers (aged 15-18 years). Results showed that 6 participants had full MS, 2 had high fasting blood glucose values (>7.0 mmol/L), 55 had high adiposity, and 21 had insulin resistance. Assessment of the components of MS by body mass index (BMI) status showed that obese participants (n = 29) had a high prevalence (86.2% had one or more component), whereas only 10.5% of those with healthy BMI status (n = 19) had any MS component. Elevated fat mass had substantial effects on fasting insulin values, HOMA2, and the McAuley index because in data adjusted for age, sex, and lean mass, a 10% greater fat mass was associated with a 4.7% increase in fasting insulin, a 5.3% rise in HOMA2, and a 2.3% decrease in the McAuley index. Our results suggest that the antecedents of cardiovascular disease and type 2 diabetes mellitus occur frequently in young Pacific Islanders having high adiposity. We conclude that community studies of PI adolescents should focus on assessing risk factors whenever BMI values are high.

Association of +45G15G(T/G) and +276(G/T) polymorphisms in the ADIPOQ gene with polycystic ovary syndrome among Han Chinese women

Polycystic ovary syndrome (PCOS) is frequently associated with insulin resistance (IR) and consequently with increased risk of metabolic disorders. Adiponectin is the most abundant adipocytokine and may play a role in the regulation of insulin sensitivity and IR in PCOS. The aim of the present study was to evaluate the genetic influence of the adiponectin (ADIPOQ) gene polymorphisms in the development of PCOS among Han Chinese women. Two single nucleotide polymorphisms (SNPs),+45G15G(T/G) and +276(G/T), in the ADIPOQ gene were genotyped in 120 patients with PCOS and 120 healthy control subjects. All of them were Han Chinese women. Both SNPs were found to be significantly associated with PCOS (P=0.021, odds ratios=1.629, 95% confidence intervals: 1.074-2.469 and P=0.015, 1.576, 1.091-2.279 respectively). In SNP +276(G/T), the allele G was found to be significantly associated with increased fasting insulin levels, homeostasis model assessment to assess IR index, and area under the curve glucose levels, but decreased glucose and insulin ratio in the PCOS patients. Furthermore, the patients carrying genotypes G/G and G/T had significantly decreased levels of serum adiponectin (6.16+/-3.18 plus 5.93+/-3.23 vs 8.96+/-3.21 microg/ml, P=0.030) compared with the patients with genotype T/T. The present study provides evidence that SNPs +45G15G(T/G) and +276(G/T) in the ADIPOQ gene are associated with PCOS in Han Chinese women. SNP +276(G/T) may contribute to an impact of insulin levels and IR, which are implicated in the susceptibility for PCOS.

Reduced postprandial proinsulinaemia and 32–33 split proinsulinaemia after a mixed meal in type 2 diabetic patients following sensitization to insulin with pioglitazone

Reduced insulin sensitivity associated with fasting hyperproinsulinaemia is common in type 2 diabetes. Proinsulinaemia is an established independent cardiovascular risk factor. The objective was to investigate fasting and postprandial release of insulin, proinsulin (PI) and 32-33 split proinsulin (SPI) before and after sensitization to insulin with pioglitazone compared to a group treated with glibenclamide. A randomized double-blind placebo-controlled trial. Twenty-two type 2 diabetic patients were recruited along with 10 normal subjects. After 4 weeks washout, patients received a mixed meal and were assigned to receive pioglitazone or glibenclamide for 20 weeks, after which patients received another identical test meal. The treatment regimes were designed to maintain glycaemic control (HbA1c) at pretreatment levels so that beta-cells received an equivalent glycaemic stimulus for both test meals. Plasma insulin, PI, SPI and glucose concentrations were measured over an 8-h postprandial period. The output of PI and SPI was measured as the integrated postprandial response (area under the curve, AUC). Pioglitazone treatment resulted in a significant reduction in fasting levels of PI and SPI compared to those of the controls. Postprandially, pioglitazone treatment had no effect on the insulin AUC response to the meal but significantly reduced the PI and SPI AUCs. Glibenclamide increased fasting insulin and the postprandial insulin AUC but had no effect on the PI and SPI AUCs. Sensitization to insulin with pioglitazone reduces the amount of insulin precursor species present in fasting and postprandially and may reduce cardiovascular risk.

Identification of a functional protein kinase Cβ promoter polymorphism in humans related to insulin resistance

Protein kinase Cβ (PKCβ) is known to inhibit insulin production in β-cells and to support insulin action in skeletal muscle. We therefore searched for functional polymorphisms among already known genetic variants in the PKCβ promoter and investigated their relation to glucose metabolism in humans. We found that the gene variant in the PKCβ promoter at position −546 significantly reduced promoter activity in functional assays ( P < 0.05). Human subjects carrying this variant had a 3.5-fold decrease in PKCβ2-protein expression in their thrombocytes ( P = 0.006). Additionally, we tested whether this variant affects parameters of glucose metabolism using 1012 humans included into the MeSyBePo study (Metabolic Syndrome Berlin Potsdam). The −546 variant was highly significant associated with increased homeostasis model assessment for insulin resistance (HOMA-IR, P = 0.009) in the cohort. This association was accompanied by significantly increased fasting insulin concentrations in carriers of the homozygous polymorphism ( P = 0.021). Our results suggest that the −546 polymorphism in the PKCβ promoter reduces promoter activity, which leads to a decreased expression of PKCβ2 and subsequently is associated with decreased peripheral insulin-dependent glucose uptake.

Characterization of the Influence of Vildagliptin on Model-Assessed β-Cell Function in Patients with Type 2 Diabetes and Mild Hyperglycemia

This study was conducted to characterize the effects of vildagliptin on beta-cell function in patients with type 2 diabetes and mild hyperglycemia. A 52-wk double-blind, randomized, parallel-group study comparing vildagliptin (50 mg every day) and placebo was conducted in 306 patients with mild hyperglycemia (glycosylated hemoglobin of 6.2-7.5%). Plasma glucose and C-peptide levels were measured during standard meal tests performed at baseline, wk 24 and 52, and after 4-wk washout. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution, and beta-cell function was quantified with a mathematical model that describes ISR as a function of absolute glucose levels (insulin secretory tone and glucose sensitivity), the glucose rate of change (rate sensitivity), and a potentiation factor. Vildagliptin significantly increased fasting insulin secretory tone [between-group difference in adjusted mean change from baseline to wk 52 (AM Delta) = +34.1 +/- 9.5 pmol.min(-1).m(-2), P < 0.001] glucose sensitivity (AM Delta = +20.7 +/- 5.2 pmol.min(-1).m(-2).mm(-1), P < 0.001), and rate sensitivity (AM Delta = +163.6 +/- 67.0 pmol.m(-2).mm(-1), P = 0.015), but total insulin secretion (ISR area under the curve at 0-2 h) and the potentiation factor excursion during meals were unchanged. These improvements in beta-cell function were accompanied by a decrease in the glucose area under the curve at 0-2 h (AM Delta = -1.7 +/- 0.5 mm/h, P = 0.002) and in glycosylated hemoglobin (AM Delta = -0.3 +/- 0.1%, P < 0.001). None of the effects of vildagliptin remained after 4-wk washout from study medication. Consistent with previous findings from shorter-term studies in patients with more severe hyperglycemia, in patients with mild hyperglycemia, improved beta-cell function is maintained throughout 52-wk treatment with vildagliptin and underlies a sustained improvement in glycemic control. However, no effects remain after washout.

Effects of Simvastatin and Oral Contraceptive Agent on Polycystic Ovary Syndrome: Prospective, Randomized, Crossover Trial

There is increasing evidence that statins improve the lipid profile and also have cardioprotective effects that include an anti-inflammatory action and improved endothelial dysfunction. Preliminary findings from a 12-week trial suggest that women with polycystic ovary syndrome (PCOS) had lower total testosterone levels and a better lipid profile when given simvastatin plus an oral contraceptive pill (OCP) rather than an OCP alone. The final results of this trial, after a crossover of treatments and follow-up for 24 weeks, now are available. The 48 women entered into the study were prospectively randomized to receive simvastatin plus OCP for 12 weeks followed by OCP alone for 12 weeks longer, or OCP alone for 12 weeks and then combined treatment. Simvastatin was given orally in a daily dose of 20 mg. The OCP contained 20 μg of ethinyl estradiol and 150 μg of desogestrelpo. Total serum testosterone declined 38% after combined treatment but only by 26% with OC alone, a highly significant difference. The corresponding figures for free testosterone levels were 58% and 35%. Hirsutism decreased by about 8% with combined treatment and by less than 5% with OCP treatment; this difference also was significant. Similar effects on levels of dehydroepiandrosterone sulfate accompanied the two treatment regimens. Simvastatin therapy correlated with decreased levels of luteinizing hormone, but no changes in follicle-stimulating hormone or prolactin. Total cholesterol decreased by 7.5% with combined treatment but increased modestly on OCP alone. Both treatments were associated with increases in high-density lipoprotein cholesterol. With combined treatment, low-density lipoprotein cholesterol decreased by 20%. Triglycerides did not change with combined treatment but rose by one-fifth on OCP alone. OCP treatment led to a modest but significant negative effect on glucose metabolism. Both combined treatment and OCP correlated with a significant increase in fasting insulin. Statin therapy significantly improved markers of systemic inflammation including high-sensitivity C-reactive protein and soluble vascular cell adhesion molecule. No significant changes in body mass index were noted, and none of the subjects developed symptoms of muscle damage or biochemical evidence of liver dysfunction. These findings show that simvastatin therapy can substantially lessen clinical and endocrinological elements of PCOS and, at the same time, decrease cardiovascular risk factors.

Attenuation of type 2 diabetes mellitus in the male Zucker diabetic fatty rat: the effects of stress and non-volitional exercise

To date, a limited number of studies have investigated the effects of exercise on the maintenance of endocrine pancreatic adaptations to worsening insulin resistance. In particular, the roles of stress hormones that are associated with commonly used forced-exercise paradigms are not fully explained. To examine the effects of exercise per se in ameliorating pancreatic decompensation over time, we investigated the role of forced swimming and sham exercise stress on the development of type 2 diabetes mellitus in the Zucker diabetic fatty (ZDF) rat. Thirty-two male ZDF rats were obtained at 5 weeks of age and all went through a 1-week acclimatization period. They were then divided into 4 groups: basal (euthanized at 6 weeks of age), exercise (1 h/d; 5 d/wk), sham exercise (sham), and non-treated controls (n = 8 per group). After 6 weeks of treatment, an intraperitoneal glucose tolerance test was performed and animals were euthanized for tissue analysis. By 5 weeks of treatment, controls had elevated fed and fasted glycemia (>11.1 and 7.1 mmol/L, respectively; both P < .05), whereas exercise and sham rats remained euglycemic. At euthanasia, there were elevations in fed insulin levels in exercise and sham rats compared with basal animals (both P < .05). Despite improvements in fed and fasting glucose levels in sham rats, glucose tolerance in sham-treated rats (intraperitoneal glucose tolerance test) was similar to controls, whereas glucose levels were similar in exercised trained and basal rats. After 6 weeks, gastrocnemius glycogen content was higher in exercised rats and sham rats when compared with age-matched controls, whereas muscle glucose transporter 4 levels were similar between groups. Compared with controls, the exercise group had increased beta cell proliferation, beta cell mass, and partial maintenance of normal islet morphology. Sham rats also displayed beta cell compensation, as evidenced by increased fasting insulin levels and partial preservation of normal islet morphology. Finally, at the time of euthanasia, plasma corticosterone was increased in sham and control rats but was at basal levels in the exercise group. In summary, both exercise and sham treatment delay the progression of type 2 diabetes mellitus in the male ZDF rat by distinct mechanisms related to pancreatic function and improvements in peripheral glucose disposal.

Veränderung des Kohlenhydratstoffwechsels und der Insulinresistenz bei Patienten mit Prader-Willi-Syndrom unter einer Wachstumshormontherapie

Life expectance and life quality have markedly changed in PWS patients within the last 10-15 years. A strict diet, improved physical activity and an additive growth hormone treatment have led to these changes. Growth hormone therapy decreases body fat and improves final height. But growth hormone also antagonizes insulin and therefore increases the diabetic potential. The purpose of our study was to investigate incidence and multiple dependencies of development of impaired carbohydrate metabolism in patients with PWS under growth hormone therapy and to determine suitable parameters for the work-up. 34 patients with genetically approved PWS have been treated with growth hormone for at least 0.5 years. The mean duration of growth hormone treatment was 2.15 years (0.5-4.51). At the start of growth hormone treatment patients were 1.33 to 16.47 years old. The clinical picture and the nutritional situation of children with PWS change age-dependent and can be divided up into three phases. The patients were duty subdivided into three age-groups at the beginning of growth hormone treatment. Group 1: 15 PWS patients, mean age 2.62 years (1.33-3.78). Group 2: 10 PWS patients, mean age 5.54 years (4.08-7.61). Group 3: 9 PWS patients, mean age 11.35 years (8.89-16.47). Data were collected within 0.3-0.38 years before start of treatment and every 6 months throughout the treatment period. Anthropometrical data, fat mass by bioelectric impedance analysis (BIA), fasting insulin, HbA1c, C-peptide, blood fats and the blood sugar profile in oral glucose tolerance tests (OGT/1.75 g glucose/kg body mass) were obtained. Growth hormone therapy was started with an average dose of 0.031 mg/kg body mass in all groups. Insulin resistance was based on Homeostasis Model Assessment-Test (HOMA). No IR or pathological OGT were detected when growth hormone therapy started before the 4th year of life. When therapy started between the 4th and 8th year, PWS patients with normal weight did not develop an IR under GH therapy. 6% developed a glucose tolerance (IGT) disorder and 4% developed an increased fasting glucose (IFG). 5 of 9 PWS patients older than 8 years at therapystart showed a transient disorder of glucose metabolism: 11% of the results obtained in these patients presented an IR with no pathological OGT, 13% showed an IR with IGT, 7% showed an IR with IFG, and 2% showed an IR with transient diabetes. For 4% the IFG persisted with no IR, for 4% the IGT persisted with no IR. These patients differed from younger ones by an increased average BMI, an increase fat body ratio and an increase fasting insulin as well as an already reached puberty. No difference was found in C-peptide, HbA1c or GH dose/kg/body mass. Transient glucose metabolism disorders with no development of manifest insulin resistance are shown by PWS patients with normal weight starting from 4th year under GH therapy. Changes in the glucose metabolism with and with no development of IR appear after start of puberty and weight increase. Changes persisted partially for 18 months. GH therapy was not interrupted for any patient, whereby physical training and dietetic measurements were increased for all patients. HOMA-index and OGT shall be used in parallel to monitor glucose metabolism as both show independently distinctive features. HbA1c and C-peptide are not suitable parameters for monitoring carbohydrate metabolism in PWS patients under GH treatment.

Nocturnal free fatty acids are uniquely elevated in the longitudinal development of diet-induced insulin resistance and hyperinsulinemia

Obesity is strongly associated with hyperinsulinemia and insulin resistance, both primary risk factors for type 2 diabetes. It has been thought that increased fasting free fatty acids (FFA) may be responsible for the development of insulin resistance during obesity, causing an increase in plasma glucose levels, which would then signal for compensatory hyperinsulinemia. But when obesity is induced by fat feeding in the dog model, there is development of insulin resistance and a marked increase in fasting insulin despite constant fasting FFA and glucose. We examined the 24-h plasma profiles of FFA, glucose, and other hormones to observe any potential longitudinal postprandial or nocturnal alterations that could lead to both insulin resistance and compensatory hyperinsulinemia induced by a high-fat diet in eight normal dogs. We found that after 6 wk of a high-fat, hypercaloric diet, there was development of significant insulin resistance and hyperinsulinemia as well as accumulation of both subcutaneous and visceral fat without a change in either fasting glucose or postprandial glucose. Moreover, although there was no change in fasting FFA, there was a highly significant increase in the nocturnal levels of FFA that occurred as a result of fat feeding. Thus enhanced nocturnal FFA, but not glucose, may be responsible for development of insulin resistance and fasting hyperinsulinemia in the fat-fed dog model.

Dyslipidemia in chronic kidney disease: Causes and consequences

Cardiovascular risk increases with each decrement in renal function. Abnormalities in plasma lipoprotein composition among patients with end-stage renal disease represent a change both in lipoprotein level and structure. Low-density lipoprotein (LDL) cholesterol is not increased and LDL level is not strongly correlated with outcome. In contrast, high-density lipoprotein (HDL) levels are decreased and are inversely associated with cardiovascular risk. HDL is decreased because of an increased rate of catabolism associated with a predominance of small dense HDL. HDL fails to mature normally as a result of decreased lecithin cholesterol ester (CE) transfer protein (lecithin:cholesterol acyltransferase), leaving CE poor, triglyceride (TG) rich HDL3, and pre β HDL. Chronic kidney disease (CKD) also causes insulin resistance, and this may also contribute to low HDL levels. Plasma TG levels are increased and TGs are found in an expanded intermediate density lipoprotein (IDL) pool. These are composed of chylomicron and very low-density lipoprotein remnants resulting from delayed lipolysis on the endothelium and impaired hepatic uptake. IDL in contrast to LDL is associated with vascular disease in dialysis patients. Lipoprotein (a) (Lp (a)) levels are also increased. In patients without renal disease. The concentration of Lp (a) is inversely associated with the size of the apolipoprotein (a) isoform inherited; Lp (a) levels are increased in patients with kidney disease as a consequence of increased concentrations, primarily of the high molecular weight isoform. Lp (a) levels are also associated with cardiovascular outcome among dialysis patients.

A study of association between common variation in the growth hormone-chorionic somatomammotropin hormone gene cluster and adult fasting insulin in a UK Caucasian population

BackgroundReduced growth during infancy is associated with adult insulin resistance. In a UK Caucasian cohort, the CSH1.01 microsatellite polymorphism in the growth hormone-chorionic somatomammotropin hormone gene cluster was recently associated with increases in adult fasting insulin of approximately 23 pmol/l for TT homozygote males compared to D1D1 or D2D2 homozygotes (P = 0.001 and 0.009; n = 206 and 92, respectively), but not for females. TT males additionally had a 547-g lower weight at 1 year (n = 270; P = 0.008) than D2D2 males. We sought to replicate these data in healthy UK Caucasian subjects. We genotyped 1396 subjects (fathers, mothers and children) from a consecutive birth study for the CSH1.01 marker and analysed genotypes for association with 1-year weight in boys and fasting insulin in fathers.ResultsWe found no evidence for association of CSH1.01 genotype with adult male fasting insulin concentrations (TT/D1D1 P = 0.38; TT/D2D2 P = 0.18) or weight at 1 year in boys (TT/D1D1 P = 0.76; TT/D2D2 P = 0.85). For fasting insulin, our data can exclude the previously observed effect sizes as the 95 % confidence intervals for the differences observed in our study exclude increases in fasting insulin of 9.0 and 12.6 pmol/l for TT relative to D1D1 and D2D2 homozygotes, respectively. Whilst we have fewer data on boys' 1-year weight than the original study, our data can exclude a reduction in 1-year weight greater than 557 g for TT relative to D2D2 homozygotes.ConclusionWe have not found association of the CSH1.01 genotype with fasting insulin or weight at 1 year. We conclude that the original study is likely to have over-estimated the effect size for fasting insulin, or that the difference in results reflects the younger age of subjects in this study relative to those in the previous study.

Development of a novel ELISA for human insulin using monoclonal antibodies produced in serum-free cell culture medium

Objectives: Development of an ELISA for human insulin that utilizes monoclonal antibodies (mAbs) produced in serum-free medium. Design and methods: Insulin mAbs were produced in vitro by hybridomas in serum-free medium. A two-step ELISA was developed to replace bovine insulin (standard) and bovine serum albumin (assay buffer) with non-animal reagents. Results: The sensitivity of the insulin ELISA was 0.73 uU/mL with a dynamic range of 2–200 uU/mL. No cross-reactivity with either human C-peptide or human proinsulin was observed. The intra- and inter-assay CVs were < 7%. The mean recovery of insulin added to plasma samples was between 102.2% and 105.7%. The mean linearity of dilution was between 93% and 110% of undiluted plasma samples. The animal serum-free (ASF) insulin ELISA showed no marked degradation of any kit component when stored at 37°C for up to 7 days. Significantly higher fasting insulin levels were observed in overweight or obese subjects ( n = 12) compared to lean subjects ( n = 10, p < 0.05). Feeding markedly increased fasting insulin levels in both lean ( p < 0.02) and overweight or obese ( p < 0.005) subjects. Excellent correlation was observed between insulin levels measured by ASF insulin ELISA and another CE marked insulin ELISA ( y = 1.06 x − 0.44, r = 1.00, n = 44). Conclusions: This novel insulin ELISA provides precision and reliability equal to methods currently used in clinical research and serves as a guide for the development of other serum-free immunoassays.

Competing Impact of Excess Weight Versus Cardiorespiratory Fitness on Cardiovascular Risk

Obesity is a risk factor for cardiovascular disease, whereas high cardiorespiratory fitness (CRF) is cardioprotective. This study evaluated the competing effect of weight and fitness on biomarkers of cardiovascular risk in a nationally representative sample of 2,112 adults (20 to 49 years of age; body mass index [BMI] > or =18.5 kg/m(2)) without previously diagnosed cardiovascular disease from the National Health and Nutrition Examination Survey 1999 to 2002. CRF levels were assigned using age- and gender-specific reference points of estimated maximal oxygen consumption calculated from submaximal graded exercise treadmill testing. CRF was also categorized by sample-specific tertiles of maximal oxygen consumption. Weight was categorized using BMI. Fasting insulin level >12.2 mU/L, C-reactive protein level > or =3.0 mg/L, and total cholesterol/high-density lipoprotein ratio (TC/HDL) >5 characterized increased cardiovascular risk. CRF and BMI were independently associated with increased fasting insulin and C-reactive protein (p <0.05). When patients with low, moderate, and high CRF were further stratified as normal, overweight, or obese, weight remained significantly associated with increased fasting insulin, C-reactive protein, and TC/HDL (p <0.001), but CRF did not. Logistic regressions evaluating increased fasting insulin, C-reactive protein, and TC/HDL demonstrated no significant differences in overweight/obese patients by CRF level after adjustment for other factors. Significant differences were present between normal-weight and overweight or obese patients regardless of fitness level. Analyses using tertiles of CRF yielded similar results. In conclusion, patients who are "fat but fit" require weight-loss interventions to improve their cardiovascular risk profiles. Future interventions should emphasize weight control, even for those with high CRF.

Haplotypes in the Lipoprotein Lipase Gene Influence Fasting Insulin and Discovery of a New Risk Haplotype

Prior studies of Mexican Americans described association of lipoprotein lipase (LPL) gene haplotypes with insulin sensitivity/resistance and atherosclerosis. The most common haplotype (haplotype 1) was protective, whereas the fourth most common haplotype (haplotype 4) conferred risk for insulin resistance and atherosclerosis. In this study of Hispanics in the Insulin Resistance Atherosclerosis Study Family Study, we sought to replicate LPL haplotype association with insulin sensitivity/resistance. LPL haplotypes based on 12 single nucleotide polymorphisms were analyzed for association with indexes of insulin sensitivity and other metabolic and adiposity measures. This study was conducted in the general community of San Antonio, Texas, and San Luis Valley, Colorado. Participants in this study were 978 members of 86 Hispanic families. LPL haplogenotype, metabolic phenotypes, and adiposity were measured in this study. The haplotype structure was identical with that observed in prior studies. Among 978 phenotyped subjects, haplotype 1 was associated with decreased fasting insulin (P = 0.01), and haplotype 4 was associated with increased fasting insulin (P = 0.02) and increased visceral fat mass (P = 0.002). Insulin sensitivity, derived from iv glucose tolerance testing, tended (P > 0.1) to be higher with haplotype 1 (S(I) = 1.72) and lower with haplotype 4 (S(I)=1.38). Haplotype 2 was associated with increases in fasting insulin, triglycerides (TGs), TG to high-density lipoprotein-cholesterol ratio, and apolipoprotein B (P = 0.01-0.04). This study independently replicates our prior results of LPL haplotypes 1 and 4 as associated with measures of insulin sensitivity and resistance, respectively. Haplotype 4 may confer insulin resistance by increasing visceral fat. Haplotype 2 was identified as a new risk haplotype, suggesting the complex nature of LPL's effect on features of the insulin resistance syndrome.

Aminotransferase activity in morbid and uncomplicated obesity: Predictive role of fasting insulin

Background and aims. An elevation in liver enzymes and, most notably, high serum alanine aminotransferase (ALT) activity, has been correlated with metabolic syndrome and obesity. However, whether obesity per se or obesity-related co-morbidities affect aminotransferase activity is still unclear. In this study we sought to evaluate serum aminotransferase activity in morbid and uncomplicated obese subjects Methods. In this cross-sectional study, serum aminotransferase activity, anthropometric and metabolic parameters were assessed in 290 morbid and 105 uncomplicated consecutive obese subjects matched for body mass index (BMI) (40.1 ± 6.8 vs. 39.9 ± 8.3 kg/m 2, respectively), age (35.9 ± 10 vs. 34.8 ± 9.6 years, respectively), sex distribution and duration of obesity. Results. Uncomplicated obese subjects showed significantly lower serum ALT activity (17.58 ± 6.3 (range 10–39) vs. 23.43 ± 16 (range 12–89) U/l, ( p < 0.001)), and lower aspartate aminotransferase (AST), AST/ALT ratios and gamma-glutamyltranspeptidase (γGT) ( p < 0.01 for all) than morbid obese subjects. Only 11% women and 19% men in the uncomplicated obese group showed high ALT levels, while ALT activity was high in 48% women and 51% men in the morbid obese group. Fasting insulin was the best correlate of ALT activity ( R 2 = 0.21, p = 0.003). Conclusions. Our findings show that elevated ALT and AST activity are associated with increased fasting insulin and not with obesity per se, suggesting that the presence of insulin resistance, rather than BMI alone, plays a role in mediating the increased aminotransferase activity.

A one-year study comparing the efficacy and safety of rosiglitazone and glibenclamide in the treatment of type 2 diabetes

Background and aim This study was designed to compare the efficacy of rosiglitazone and glibenclamide in individuals with type 2 diabetes over a 12-month period. Methods and results A total of 598 patients were randomized to double-blind treatment for 52 weeks with rosiglitazone 4 mg/d ( n = 200), rosiglitazone 8 mg/d ( n = 191) or glibenclamide ( n = 207; dose adjusted up to 15 mg/d over the first 12 weeks according to clinical response). Changes in fasting plasma glucose (FPG), haemoglobin A 1c (HbA 1c), fasting insulin and its precursor peptides, and lipids were measured and safety was evaluated. Significant reductions in HbA 1c levels at 52 weeks compared with baseline were seen in all treatment groups (rosiglitazone 4 mg/d = −0.3%, P = 0.0003; rosiglitazone 8 mg/d = −0.5%, P < 0.0001; glibenclamide = −0.7%, P < 0.0001). Mean FPG levels were also significantly reduced in all treatment groups (rosiglitazone 4 mg/d = −1.4 mmol/l; rosiglitazone 8 mg/d = −2.3 mmol/l; glibenclamide = −1.7 mmol/l; P < 0.0001 vs. baseline for all treatments). Rosiglitazone therapy reduced plasma insulin, proinsulin, split proinsulin and free fatty acid levels compared with glibenclamide. Rosiglitazone improved insulin resistance while a worsening was seen with glibenclamide. Total:high-density lipoprotein cholesterol ratios were reduced with glibenclamide and unchanged with rosiglitazone. All treatments were generally well tolerated. Conclusions The efficacy of rosiglitazone 8 mg/d in improving glycaemic control in patients with type 2 diabetes is comparable to that of glibenclamide. However, rosiglitazone reduced insulin resistance and proinsulin levels whereas glibenclamide use was associated with an increase in fasting insulin and proinsulin. This suggests that in the long term, rosiglitazone may protect the β-cell whereas glibenclamide is likely to increase the burden.

Leptin prevents insulin resistance induced by conjugated linoleic acid in obese mice

The dietary fatty acid conjugated linoleic acid (CLA) reduces adipose mass and enhances insulin sensitivity in several animal models. Conversely, in some rodent models, CLA induces lipodystrophy, insulin resistance, and reduces adipokines. Leptin is an insulin sensitizing adipokine that may work by suppressing steatosis in liver and muscle, a condition that may contribute to insulin resistance. Therefore, we hypothesize that leptin prevents CLA-induced insulin resistance in obese mice by attenuating steatosis. In a 2x2 factorial design, 6-week old, male ob/ob mice were fed either a control diet or a diet supplemented with 1.5% mixed isomer CLA and received daily intraperitoneal injections of either PBS or 10 mg/kg leptin for 4 weeks. CLA and leptin alone or in combination decreased weight gain, which was reflected by a reduction of epididymal fat mass. At 2 and 4 weeks of feeding, leptin treatment significantly attenuated CLA-induced increased fasting glucose, and at 4 weeks, leptin prevented CLA-induced impairment of insulin tolerance. Although CLA alone significantly increased fasting insulin, leptin reduced fasting insulin levels in both control- and CLA-fed mice. Concentrations of liver and muscle triglycerides (TG) were not altered by CLA alone; however, when adjusted for tissue mass and body weight, CLA alone increased hepatic, but not muscle, TG levels. Leptin reduced liver and muscle TG concentrations in both diet groups, and when adjusted for liver mass and body weight. These data suggest that the restoration of insulin sensitivity by leptin may partially be attributed to the reduction of total hepatic TG in obese mice fed CLA.