Abstract Objective To examine whether individuals with normal glucose tolerance (NGT), whose 1-h post-load plasma glucose is ≥155 mg/dl, or with impaired glucose tolerance (IGT) have an increased ...carotid intima–media thickness (IMT), as compared with NGT individuals with 1-h post-load plasma <155 mg/dl. Methods Atherosclerosis risk factors, oral glucose tolerance test (OGTT), and ultrasound manual measurement of IMT were analyzed in 400 non-diabetic Caucasians. Results As compared with individuals with a 1-h post-load plasma glucose <155 mg/dl, NGT individuals with a 1-h post-load plasma glucose ≥155 mg/dl exhibited higher hsCRP (2.0 ± 1.5 vs. 1.5 ± 1.0, P = 0.008), and IMT (0.82 ± 0.20 vs. 0.71 ± 0.16; P = 0.006), and lower insulin sensitivity (71 ± 39 vs. 105 ± 57; P < 0.0001), and IGF-1 levels (214 ± 88 vs. 176 ± 49; P < 0.03). No significant differences were observed in metabolic and cardiovascular risk factors between IGT and NGT subjects with a 1-h post-load glucose ≥155 mg/dl. Of the three glycemic parameters, 1-h and 2-h post-load glucose, but not fasting glucose, were significantly correlated with IMT. In a stepwise multivariate regression analysis in a model including age, gender, and a variety of atherosclerosis risk factors, the three variables that remained significantly associated with IMT were age ( P < 0.0001), BMI ( P < 0.0001), and 1-h post-load glucose ( P = 0.02) accounting for 20.2% of its variation. Conclusions NGT subjects with a 1-h post-load glucose ≥155 mg/dl have an atherogenic profile similar to IGT individuals. These data suggest that a cutoff point of 155 mg/dl for the 1-h post-load glucose during OGTT may be helpful in the identification of NGT subjects at increased risk for cardiovascular disease.
Abstract Aim Endoplasmic reticulum (ER) stress is implicated in the pathogenesis of several human disorders, including cardiovascular disease (CVD). CVD recognizes endothelial dysfunction (ED) as its ...pathogenetic primum movens ; interestingly a large body of evidence has identified the unchecked ER stress response as a main actor in vascular damage elicited by various cardio-metabolic risk factors. In the present Review, we summarize findings from experimental studies on the ER stress-related ED, focusing on the mechanisms underlying this association. Data synthesis Different noxious agents, such as hyperhomocysteinemia, hyperlipidemia, hyperglycemia and chronic inflammation, induce ED promoting an amplified ER stress response as demonstrated by several studies in animal models, as well as in human primary and immortalized endothelial cells. ER stress represents therefore a key mediator of vascular damage, operating in a setting of increased inflammatory burden and oxidative stress, thus contributing to foster a vicious pathogenic cycle. Conclusions Experimental studies summarized in this Review strongly suggest that an unchecked ER stress response plays a central role in the pathogenesis of ED and, consequently, CVD. Counteracting ER stress may thus represent a promising, even if largely unexplored as-yet, therapeutic approach aimed to prevent vascular damage, slowing the progression from ED to cardiovascular events.
Insulin receptor substrate (IRS) molecules are key mediators in insulin signaling and play a central role in maintaining basic cellular functions such as growth, survival, and metabolism. They act as ...docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 (SH2) domains. Four members (IRS‐1, IRS‐2, IRS‐3, IRS‐4) of this family have been identified that differ as to tissue distribution, subcellu‐lar localization, developmental expression, binding to the insulin receptor, and interaction with SH2 domain‐containing proteins. Results from targeted disruption of the IRS genes in mice have provided important clues to the functional differences among these related molecules, suggesting they play different and specific roles in vivo. The available data are consistent with the notion that IRS‐1 and IRS‐2 are not functionally interchangeable in tissues that are responsible for glucose production (liver), glucose uptake (skeletal muscle and adipose tissue), and insulin production (pancreatic β cells). In fact, IRS‐1 appears to have its major role in skeletal muscle whereas IRS‐2 appears to regulate he‐patic insulin action as well as pancreatic β cell development and survival. By contrast, IRS‐3 and IRS‐4 genes appear to play a redundant role in the IRS signaling system. Defects in muscle IRS‐1 expression and function have been reported in insulin‐resistant states such as obesity and type 2 diabetes. Several polymorphisms in the IRS genes have been identified, but only the Gly→Arg972 substitution of IRS‐1, interacting with environmental factors, seems to have a patho‐genic role in the development of type 2 diabetes. In contrast, polymorphisms of the other IRS genes do not appear to contribute to type 2 diabetes.—Sesti, G., Federici, M., Hribal, M. L., Lauro, D., Sbraccia, P., Lauro, R. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J. 15, 2099–2111 (2001)
Aims/hypothesis We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. Methods ...Non-diabetic offspring (n = 874; mean age 40 ± 10.4 years; BMI 26.6 ± 4.9 kg/m²) of type 2 diabetic patients from five different European Centres (Denmark, Finland, Germany, Italy and Sweden) were examined with regard to insulin sensitivity (euglycaemic clamps), insulin release (IVGTT) and glucose tolerance (OGTT). The levels of glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) were measured during the OGTT in 278 individuals. Results Normal glucose tolerance was found in 634 participants, while 110 had isolated IFG, 86 had isolated IGT and 44 had both IFG and IGT, i.e. about 28% had a form of reduced glucose tolerance. Participants with isolated IFG had lower glucose-corrected first-phase (0-10 min) and higher second-phase insulin release (10-60 min) during the IVGTT, while insulin sensitivity was reduced in all groups with abnormal glucose tolerance. Similarly, GLP-1 but not GIP levels were reduced in individuals with abnormal glucose tolerance. Conclusions/interpretation The primary mechanism leading to hyperglycaemia in participants with isolated IFG is likely to be impaired basal and first-phase insulin secretion, whereas in isolated IGT the primary mechanism leading to postglucose load hyperglycaemia is insulin resistance. Reduced GLP-1 levels were seen in all groups with abnormal glucose tolerance and were unrelated to the insulin release pattern during an IVGTT.
Insulin-like growth factors promote myoblast differentiation through phosphoinositol 3-kinase and Akt signaling. Akt substrates required for myogenic differentiation are unknown. Forkhead ...transcription factors of the forkhead box gene, group O (Foxo) subfamily are phosphorylated in an insulin-responsive manner by phosphatidylinositol 3-kinase-dependent kinases. Phosphorylation leads to nuclear exclusion and inactivation. We show that a constitutively active Foxo1 mutant inhibits differentiation of C2C12cells and prevents myotube differentiation induced by constitutively active Akt. In contrast, a transcriptionally inactive mutant Foxo1 partially rescues inhibition of C2C12differentiation mediated by wortmannin, but not by rapamycin, and is able to induce aggregation-independent myogenic conversion of teratocarcinoma cells. Inhibition of Foxo expression by siRNA resulted in more efficient differentiation, associated with increased myosin expression. These observations indicate that Foxo proteins are key effectors of Akt-dependent myogenesis.
Aims/hypothesis The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in ...three samples of white people with European ancestry. Methods Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay. Results The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (−35.09 95% CI 14.68-55.52, p = 0.0008 for CC+CT vs TT; and −29.45 95% CI 9.51-49.38, p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 95% CI 1.20-1.95 for the meta-analysis of the three samples). Conclusions/interpretation Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.
Abstract Background and aims Nonalcoholic fatty liver disease (NAFLD) is linked with insulin resistance, however, if it is differentially associated with surrogate hepatic insulin resistance indexes ...is still undefined. We examined the relationship between these indexes, NAFLD and its related biomarkers (alanine aminotransferase ALT, aspartate aminotransferase AST, gamma-glutamyltransferase GGT, alkaline phosphatase ALK, high-sensitive C reactive protein hsCRP, insulin-like growth factor-1 IGF-1). Methods and results 473 Caucasians subjects underwent liver ultrasonography and oral glucose tolerance tests; homeostasis model assessment (HOMA), glucose0–30 (area under the curve AUC) × insulin0–30 (AUC) and liver insulin resistance (liver IR) indexes were computed. Liver IR index correlated more strongly than HOMA with GGT, ALK, hsCRP, ALT and AST and more strongly than glucose0–30 (AUC) × insulin0–30 (AUC) index with ALT, AST, GGT, ALK, hsCRP, and IGF-1. The ability of these indexes to identify NAFLD was evaluated by the area under the ROC curve; the ROC AUC for liver IR index was higher (0.733) than the ones for HOMA (0.685) and glucose0–30 (AUC) × insulin0–30 (AUC) (0.663) indexes. In a logistic regression model subjects in the highest quartile of the three indexes had a higher risk of having NAFLD than those in the lowest quartile (9.85-, 5.12- or 3.99-fold higher for liver IR index, HOMA, glucose0–30 (AUC) × insulin0–30 (AUC) index respectively). Conclusions we documented significant cross-sectional associations of NAFLD and liver biomarkers with three validated indexes of hepatic insulin resistance, with liver IR index showing the stronger correlation.
Abstract Background and aims To evaluate if complement C3 is associated with insulin secretion, as suggested by recent in vitro studies, independently of confounders including adiposity measures. ...Methods and results 1010 nondiabetic subjects were stratified into quartiles according to complement C3 values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT) in the whole study group and from intravenous glucose tolerance test (IVGTT) in a subgroup (n = 110). Significant differences between quartiles of C3 were observed in body mass index (BMI), waist, fat mass, blood pressure, total cholesterol, high density lipoprotein (HDL), triglycerides, fasting and 2-h post-load glucose, fasting insulin, C reactive protein (hsCRP), fibrinogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT), complement C4, and insulin sensitivity with C3 quartiles exhibiting graded increases in cardio-metabolic risk factors. Differences in insulin secretion indexes between C3 quartiles remained significant after adjustment for age, gender, BMI, insulin sensitivity, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, and complement C4 levels ( P < 0.0001). A multivariable regression analysis revealed that complement C3 is a contributor of insulin secretion, explaining 2.4% and 1.9% of variation of the Stumvoll index for first-phase and second-phase insulin secretion, respectively, and 2.1% of variation of the InsAUC30/GluAUC30 index, independently of gender, age, BMI, waist, fat mass, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, AST, ALT. Conclusions Complement C3 concentrations are associated with insulin secretion independently of important determinants of glucose homeostasis such as gender, age, adiposity, subclinical inflammation, and insulin sensitivity.
Aims/hypothesis
We determined the contribution to insulin resistance of the PH domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates Akt at Ser473, inhibiting its activity. ...We measured the abundance of PHLPP in fat and skeletal muscle from obese participants. To study the effect of PHLPP on insulin signalling,
PHLPP
(also known as
PHLPP1
) was overexpressed in HepG2 and L6 cells.
Methods
Subcutaneous fat samples were obtained from 82 morbidly obese and ten non-obese participants. Skeletal muscle samples were obtained from 12 obese and eight non-obese participants. Quantification of PHLPP-1 in human tissues was performed by immunoblotting. The functional consequences of recombinant
PHLPP1
overexpression in hepatoma HepG2 cells and L6 myoblasts were investigated.
Results
Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. PHLPP-1 abundance was twofold higher in the three obese groups than in non-obese participants (
p
= 0.004). No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. PHLPP-1 abundance was correlated with basal Akt Ser473 phosphorylation (
r
= −0.48;
p
= 0.001), BMI (
r
= 0.44;
p
< 0.0001), insulin (
r
= 0.35;
p
< 0.0001) and HOMA (
r
= 0.38;
p
< 0.0001). PHLPP-1 abundance was twofold higher in the skeletal muscle of 12 obese participants than in that of eight non-obese participants (
p
< 0.0001). Insulin treatment of HepG2 cells resulted in a dose- and time-dependent upregulation of PHLPP-1. Overexpression of
PHLPP1
in HepG2 cells and L6 myoblasts resulted in impaired insulin signalling involving Akt/glycogen synthase kinase 3, glycogen synthesis and glucose transport.
Conclusions/interpretation
Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity.
Abstract Background and aims Low insulin-like growth factor-1 (IGF-1) levels and high uric acid concentrations are associated with cardio-metabolic disorders. Acute IGF-1 infusion decreases uric acid ...concentration in healthy individuals. In this study, we aimed to examine the relationship between IGF-1 and uric acid levels. Methods and results 1430 adult non diabetic subjects were stratified into quartiles according to their circulating IGF-1 values. Significant differences in uric acid concentration, measured by the URICASE/POD method were observed between low (quartile 1), intermediate (quartile 2 and 3), and high (quartile 4) IGF-1 levels groups after adjusting for age, gender, and body mass index ( P = 0.02). These differences remained significant after adjustment for blood pressure, total cholesterol, high density lipoprotein, triglycerides, fasting and 2 h post-load glucose levels, HOMA-IR index ( P = 0.005), liver enzymes ( P = 0.03), glucose tolerance status ( P = 0.02), growth hormone levels (GH) ( P = 0.05), anti-hypertensive treatments ( P = 0.04) or diuretics use ( P = 0.04)). To clarify the molecular links between IGF-1 and uric acid, we performed an in vitro study, incubating human hepatoma cells with uric acid for 24 or 48 h in the presence of GH and observed a 21% and 26% decrease, respectively, in GH-stimulated IGF-1 mRNA expression ( P = 0.02 and P = 0.012, respectively). This effect appears to be mediated by uric acid ability to down regulate GH intracellular signaling; in fact we observed a significant decrease of GH activated JAK2 and Stat5 phosphorylation. Conclusions These data demonstrate an inverse relationship between IGF-1 and uric acid levels in adults and suggest that uric acid might affect hepatic IGF-1 synthesis.
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