Nonalcoholic fatty liver disease is associated with a decreased myocardial mechano-energetic efficiency.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is linked to a raised risk of cardiovascular diseases (CVD), although the underlying mechanisms are not completely known. A reduced myocardial mechano-energetic efficiency (MEE) has been found to be an independent predictor of CVD. OBJECTIVE: To evaluate the association between NAFLD and a compromised MEE. METHODS: Myocardial MEE was assessed by a validated echocardiography-derived measure in 699 nondiabetic individuals subdivided into two groups according to ultrasonography defined presence of NAFLD. RESULTS: Subjects with NAFLD displayed higher levels of systolic (SBP) and diastolic blood pressure (DBP), triglycerides, fasting and postload glucose, high-sensitivity C-reactive protein (hsCRP), insulin resistance (IR) estimated by HOMA-IR and liver IR index, and lower values of high-density lipoprotein (HDL) in comparison with those without NAFLD. Presence of NAFLD was associated with increased levels of myocardial oxygen demand and reduced values of MEE. MEE was negatively correlated with male sex, age, BMI, waist circumference, SBP, DBP, total cholesterol, triglycerides, fasting and postload glucose, HOMA-IR and liver IR index, hsCRP and positively with HDL levels. In a multivariable regression analysis, presence of NAFLD was associated with MEE regardless of several cardio-metabolic risk factors such as age, gender, waist circumference, SBP, DBP, total and HDL cholesterol, triglycerides, glucose tolerance and hsCRP (ß = -0.09, P = 0.04), but not independently of IR estimates. CONCLUSION: Ultrasound-defined presence of NAFLD is associated with a decreased MEE, a predictor of adverse cardiovascular events. The relationship between NAFLD and a compromised MEE is dependent of IR.

Hemorheological alterations in adults with prediabetes identified by hemoglobin A1c levels.

BACKGROUND AND AIMS: A link between increased blood viscosity and type 2 diabetes has been previously reported. Herein, we investigated the association of blood viscosity with prediabetes, identified by glycated hemoglobin A1c (HbA1c) according to the new American Diabetes Association criteria, and subclinical atherosclerosis. METHODS AND RESULTS: The study cohort includes 1136 non-diabetic adults submitted to anthropometrical evaluation, an oral glucose tolerance test and ultrasound measurement of carotid intima-media thickness (IMT). Whole blood viscosity was estimated using a validated formula based on hematocrit and total plasma proteins. After adjusting for age, and gender, individuals with HbA1c-defined prediabetes (HbA1c 5.7-6.4% [39-47 mmol/mol]) exhibited significantly higher values of hematocrit, and predicted blood viscosity as compared with controls. Increased levels of IMT were observed in subjects with HbA1c-defined prediabetes in comparison to controls. Predicted blood viscosity was positively correlated with age, waist circumference, blood pressure, cholesterol, triglycerides, fibrinogen, white blood cell, HbA1c, fasting and 2-h post-load glucose levels, fasting insulin, IMT and inversely correlated with HDL and Matsuda index of insulin sensitivity. Of the three glycemic parameters, i.e. HbA1c, fasting and 2-h post-load glucose, only HbA1c showed a significant correlation with predicted blood viscosity (ß = 0.054, P = 0.04) in a multivariate regression analysis model including multiple atherosclerosis risk factors. CONCLUSION: The study shows that individuals with HbA1c-defined prediabetes have increased predicted blood viscosity and IMT. The HbA1c criterion may be helpful to capture individuals with an increased risk of diabetes and cardiovascular disease who may benefit from an intensive lifestyle intervention.

Liraglutide improves cardiac function in patients with type 2 diabetes and chronic heart failure.

PURPOSE: To compare the effect of liraglutide, sitagliptin and insulin glargine added to standard therapy on left ventricular function in post-ischemic type-2 diabetes mellitus patients. METHODS: We evaluated 32 type-2 diabetes mellitus Caucasians with history of post-ischemic chronic heart failure NYHA class II/III and/or left ventricular ejection fraction ≤45 %. Participants underwent laboratory determinations, electrocardiogram, echocardiogram, Minnesota Living with Heart Failure questionnaire and 6 min walking test at baseline and following 52 weeks treatment. Patients were treated with standard therapy for chronic heart failure and were randomized to receive liraglutide, sitagliptin and glargine in addition to metformin and/or sulfonylurea. RESULTS: Liraglutide treatment induced an improvement in left ventricular ejection fraction from 41.5 ± 2.2 to 46.3 ± 3 %; P = 0.001). On the contrary, treatment with sitagliptin and glargine induced no changes in left ventricular ejection fraction (41.8 ± 2.6 vs. 42.5 ± 2.5 % and 42 ± 1.5 vs. 42 ± 1.6 %, respectively; P = NS). Indexed end-systolic LV volume was reduced only in liraglutide-treated patients (51 ± 9 vs. 43 ± 8 ml/m2; P < 0.05). Liraglutide treatment induced also a significant increase in the anterograde stroke volume (39 ± 9 vs. 49 ± 11 ml; P < 0.05), whereas no differences were observed in the other two groups. Cardiac output and cardiac index showed a significant increase only in liraglutide-treated patients (4.4 ± 0.5 vs. 5.0 ± 0.6 L/min; P < 0.05 and 1.23 ± 0.26 vs. 1.62 ± 0.29 L/m2; P = 0.005, respectively). Liraglutide treatment was also associated with an improvement of functional capacity and an improvement of quality of life. CONCLUSIONS: These data provide evidence that treatment with liraglutide is associated with improvement of cardiac function and functional capacity in failing post-ischemic type-2 diabetes mellitus patients.

Dietary patterns and 1-h post-load glucose in essential hypertension.

BACKGROUND AND AIMS: Normoglucosetolerants (NGT) are considered at low risk, even if a 1-h post-load glucose (PLG) value ≥ 155 mg dl(-1) identifies NGTs at high risk of type-2 diabetes (T2D) and sub-clinical organ damage. Specific dietary factors may affect insulin sensitivity and the risk of T2D. However, it is unknown whether dietary components affect 1-h PLG in hypertensive NGT. Therefore, we investigate the effect of dietary patterns on 1-h PLG. METHODS AND RESULTS: We selected 188 subjects (94 NGTs < 155 mg dl(-1) and 94 NGTs ≥ 155 mg dl(-1) PLG), well matched for age, gender and body mass index (BMI). Insulin sensitivity was evaluated using the Matsuda index. Dietary intake was quantified by a semiquantitative food frequency questionnaire (FEQ) validated in the European Investigation into Cancer and Nutrition (EPIC) study. The NGT ≥ 155 group had significantly reduced insulin sensitivity (40.3 ± 19.8 vs. 73.3 ± 28.8; P < 0.0001). With the exclusion of total calories, lipids, alcohol and fiber consumption we observed a significant difference, between groups, in starch (214.1 ± 52.4 vs. 268.8 ± 71.8 g; P < 0.0001), saturated (27.4 ± 8.7 vs. 24.1 ± 8.5 g; P = 0.009), monounsaturated (45.5 ± 8.9 vs. 48.8 ± 10.7 g; P = 0.023) and polyunsaturated fatty acids (FAs) (14.5 ± 4.0 vs. 16.8 ± 4.7 g; P < 0.0001), fructose (14.5 ± 5.3 vs. 11.2 ± 4.8 g; P < 0.0001), and oligosaccharides (103.2 ± 26.6 vs. 89.9 ± 29.2 g; P = 0.001) consumption. In the whole population, starch was the major predictor of 1-h PLG, explaining 23.2% of variation (P < 0.0001). In the NGT < 155 group, fructose was the strongest predictor, accounting for 15.4% of the variation; BMI, gender and polyunsaturated FAs added another 6.6%, 3.6% and 3.2%, respectively. In the NGT ≥ 155 group, saturated and polyunsaturated FAs were retained as the major predictors of 1-h PLG, explaining 18.2% and 11.4% of the variation. CONCLUSIONS: The present data demonstrate that dietary patterns affect 1-h PLG, remarking the importance of both quantitative and qualitative composition of a diet.

Insulin sensitivity, and ß-cell function in relation to hemoglobin A1C.

BACKGROUND AND AIMS: The A1C diagnostic criterion for identifying individuals at increased risk for diabetes, introduced by the American Diabetes Association in 2010, was not defined on the basis of the principal pathophysiological abnormalities responsible for the development and progression of type 2 diabetes; we therefore wished to gain a deeper insight into the metabolic abnormalities characterizing the group of at risk individuals with an A1C value of 5.7-6.4%. METHODS AND RESULTS: As many as 338 non-diabetic offspring of type 2 diabetic patients were consecutively recruited. Insulin secretion was assessed using both indexes derived from oral glucose tolerance test (OGTT), and intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp. As compared with subjects with A1C <5.7%, individuals with A1C of 5.7-6.4% exhibited lower insulin sensitivity after adjusting for age, gender and body mass index (BMI). Insulin secretion estimated from the OGTT, did not differ between the two groups. By contrast, as compared with subjects with A1C <5.7%, the acute insulin response (AIR) during an IVGTT and both IVGTT-derived and OGTT-derived disposition indexes were reduced in individuals with A1C of 5.7-6.4% after adjusting for age, gender and BMI. As A1C increased to ≥ 5.7%, a sharp decrease in insulin sensitivity and ß-cell function, measured as disposition index, was observed. CONCLUSIONS: Caucasian individuals with A1C ≥ 5.7% exhibit both core pathophysiological defects of type 2 diabetes i.e. insulin resistance and ß-cell dysfunction.

Increased carotid intima-media thickness in the physiologic range is associated with impaired postprandial glucose metabolism, insulin resistance and beta cell dysfunction.

BACKGROUND: Carotid Intima-Media Thickness (C-IMT) is a reliable predictor of cardiovascular events. We examined if increased C-IMT was associated with defects in glucose metabolism in non-diabetic subjects independently of age. METHODS: In 366 Caucasian non-diabetic subjects of the CARAMERIS study, we measured glucose response during a 75 g-Oral Glucose Tolerance Test (OGTT), insulin sensitivity index (ISI, by Matsuda Index), Liver Insulin Resistance Index (Liver-IR), insulin secretion by ΔAUC Ins0-120/Glu0-120 (ΔI/ΔG) and beta cell function (Disposition Index, DI). RESULTS: Subjects were divided in two groups according to the median age (AGE1 ≤ 45 y; AGE2 > 45 y). Only 5 subjects in AGE1 and 32 in AGE2 had C-IMT > 0.9 mm. Compared to AGE1, AGE2 had a worse cardio-metabolic profile, increased cholesterol, glucose and insulin concentrations, blood pressure and C-IMT. Both ΔI/ΔG ratio and DI were significantly reduced in AGE2. By considering tertiles of C-IMT in each AGE group (G1-G3, where G3 comprised the highest C-IMT), we found that G3 showed increased OGTT glucose profiles and Liver IR, decreased ISI and DI, compared to G1 in each AGE group. CONCLUSIONS: Increased C-IMT, but within normal ranges, is associated independently of age with altered postprandial glucose profile, increased peripheral and hepatic insulin resistance, decreased b-cell function. C-IMT measurement should become a routine analysis even in younger subjects to predict the risk of cardio-metabolic disease.

[Hyperglycaemia and Acute Coronary Syndrome]. / L'iperglicemia nelle Sindromi Coronariche Acute.

Hyperglycaemia in patients with Acute Coronary Syndrome (ACS)is common, and is an independent predictor of mortality and morbidity in patients both with and without diabetes mellitus. Hyperglycaemia may be a marker of pre-existing diabetes or glucose intolerance or may also represent a transient stress response mediated through the autonomic nervous system with release of adrenal corticosteroids and catecholamines. Several evidences suggest that an intensive control of hyperglycaemia results in a significant improvement of the adverse outcomes in the short and long term. In fact, an intensive metabolic treatment can counteract the negative effects of hyperglycaemia. However, the main difficulty to intensive glucose control in patients with ACS remains hypoglycaemia that is associated with an increased risk of mortality and myocardial re-infarction. No definitive data are available about the beneficial effects of insulin intensive treatment. Therefore, randomized multicenter clinical trials will be needed to definitively establish whether intensive glucose control will reduce the associated increased mortality rate and higher rates of complications in hospitalized ACS patients with hyperglycaemia.

Comparison of A1C, fasting and 2-h post-load plasma glucose criteria to diagnose diabetes in Italian Caucasians.

BACKGROUND AND AIMS: The American Diabetes Association (ADA) has revised criteria for diagnosis of type 2 diabetes recommending an A1C cut point of ≥6.5% in addition to criteria based on glucose levels. We compared A1C, fasting plasma glucose (FPG) or 2-h post-challenge glucose (2-hPG) criteria for the diagnosis of diabetes in a cohort of Italian Caucasians. METHODS AND RESULTS: A total of 1019 individuals without known diabetes completed an oral glucose tolerance test (OGTT) and had A1C measured. Moderate agreement existed for A1C and FPG criteria for diagnosis of type 2 diabetes (κ coefficient = 0.522), with 85.5% of individuals classified as not having diabetes by both A1C and FPG criteria, and 5.8% classified as having diabetes by both A1C and FPG criteria. Discordant classifications occurred for 5.5% of individuals who had an A1C ≥ 6.5% and FPG <126 mg dl(-1), and for 3.2% who had an A1C <6.5% and FPG ≥126 mg dl(-1). Modest agreement existed for A1C and 2-hPG criteria for diagnosis of type 2 diabetes (κ coefficient = 0.427), with 81.8% of individuals classified as not having diabetes by both A1C and 2-hPG criteria, and 6.0% classified as having diabetes by both A1C and 2-hPG criteria. The area under the receiver operating characteristic curve of A1C for identifying subjects with diabetes according to FPG or 2-hPG criteria was 0.856 and 0.794, respectively. Modest agreement existed for A1C and FPG and/or 2-hPG criteria for diagnosis of type 2 diabetes (κ coefficient = 0.446). CONCLUSIONS: A1C ≥ 6.5% demonstrates a moderate agreement with fasting glucose and 2-hPG for diagnosing diabetes among adult Italian Caucasians subjects.

One-hour post-load plasma glucose levels are associated with elevated liver enzymes.

BACKGROUND AND AIMS: Glucose-tolerant subjects who have 1-h post-load glucose levels ≥155 mg dl(-1) (normal glucose tolerance (NGT)-1h-high) are at an increased risk of developing type 2 diabetes. Prospectively conducted studies indicated that high levels of liver enzymes are predictors of a tendency to develop type 2 diabetes; however, it is unknown whether the NGT-1h-high subjects are at increased risk for secreting higher levels of liver biomarkers. METHODS AND RESULTS: In this study, oral glucose tolerance tests (OGTTs) were performed in a cohort of 1000 non-diabetic Caucasians and levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) were measured in these subjects. The NGT-1h-high subjects had increased levels of ALT and GGT, but not AST, as compared with the NGT-1h-low. Following adjustment for age and gender, the ALT, AST and GGT levels were all found to be significantly correlated with body mass index (BMI), waist circumference, blood pressure, triglycerides as well as fasting and post-challenge glucose and insulin levels. In a logistic regression analysis adjusted for age and gender, NGT-1h-high subjects were found to be at increased risk of having ALT levels in the highest quartile as compared with NGT-1h-low subjects (odds ratio (OR) = 1.71; 95% confidence interval (CI): 1.16-2.52). In addition, NGT-1 h-high subjects exhibited an increased risk for having GGT levels in the highest quartile (OR = 1.50; 95%CI: 1.02-2.17). These associations remained significant after adjustment for BMI, blood pressure and lipids, but were not significant following further adjustment for an insulin sensitivity index. NGT-1h-high subjects were at increased risk of having AST levels in the highest quartile as compared with NGT-1h-low subjects (OR = 1.51; 95%CI: 1.04-2.22). This association ceased to be significant following adjustment for BMI, blood pressure and lipids. CONCLUSIONS: These data suggest that a 1hPG ≥ 155 mg dl(-1) cut-off may facilitate the identification of NGT individuals at risk of developing liver abnormalities.

IGF-1 levels link estimated glomerular filtration rate to insulin resistance in obesity: a study in obese, but metabolically healthy, subjects and obese, insulin-resistant subjects.

BACKGROUND AND AIMS: Metabolically healthy but obese (MHO) subjects have a favourable cardio-metabolic risk profile, but whether they are also at lower risk for kidney dysfunction is still questionable. METHODS AND RESULTS: A total of 106 MHO, 122 normal-weight and 212 insulin-resistant obese (IRO) subjects were stratified on the basis of their insulin sensitivity and body mass index (BMI). The CKD-EPI equation was used to estimate glomerular filtration rate (eGFR) and ISI index was used to estimate insulin sensitivity. eGFR was significantly lower in IRO as compared to MHO subjects after adjusting for age, gender and BMI (P = 0.008). In a logistic regression model adjusted for age, gender and BMI, IRO subjects showed an increased risk of having eGFR in the lowest quartile (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.01-3.58; P = 0.04) as compared with MHO subjects. This association was maintained when waist, lean body mass, blood pressure, HDL cholesterol, triglyceride, fasting glucose and insulin levels were additionally included into the model (OR 2.49, 95%CI 1.17-5.27; P = 0.01), but its independence was not retained with further inclusion of insulin-like growth factor-1 (IGF-1) levels (OR 2.16, 95%CI 0.93-5.04; P = 0.07) No differences in eGFR were observed between non-obese and MHO individuals. CONCLUSIONS: These results indicate that heterogeneity in obese phenotypes may account for conflicting evidence regarding the significance of obesity as a risk factor for chronic kidney disease. Our findings suggest that obesity is associated with lower kidney function only when insulin sensitivity is reduced, and that plasma IGF-1 is likely to be an important mechanism linking the IRO phenotype with reduced eGFR.

[The HPA axis in the pathogenesis of chronic fatigue syndrome]. / L'asse ipotalamo-ipofi si-surrene nella patogenesi della Sindrome da Stanchezza Cronica.

Chronic fatigue syndrome (CFS) is a clinical syndrome characterized by profound disabling chronic fatigue associated with a wide array of other physical symptoms. Its etiology is currently unknown. Among the various hypotheses, considerable interest has been placed in the hypothalamus-pituitary-adrenal axis as a possible target of the pathogenesis of CFS. This article reviews the available scientific evidence about a role of hypothalamic-pituitary-adrenal axis in the pathogenesis of chronic fatigue syndrome.

Sudden progression from impaired glucose tolerance to type 2 diabetes after discontinuation of administration of anti-tumor necrosis factor-alpha antibody infliximab.

We present the case of a 45-year-old man with psoriasis and psoriatic arthritis and concomitant impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). In this patient, refractory to DMARD's, infliximab was started to control the arthritis. After achieving clinical remission of the disease, infliximab was discontinued and a 75 g- oral glucose tolerance test (OGTT) was performed. After the test, we observed a conversion from IFG/IGT glucose tolerance status to type 2 diabetes. No diet, lifestyle or therapy modifications were made during the observation period. Autoimmune diabetes was ruled out by serum antibodies determination and body weight remained constant, sustaining a protective role in infliximab in the worsening of glucose tolerance.

TRIB3 R84 variant affects glucose homeostasis by altering the interplay between insulin sensitivity and secretion.

AIMS/HYPOTHESIS: The results of studies on the genetics of complex traits need to be replicated and to reach robust statistical significance before they can be considered as established. We here tried to replicate the previously reported association between the TRIB3 Q84R polymorphism (rs2295490) and glucose homeostasis. METHODS: Three samples of Europeans with fasting glucose <7.0 mmol/l were studied. In sample 1 (n=791), the association between TRIB3 Q84R and impaired glucose regulation (IGR; defined as impaired fasting glucose and/or impaired glucose tolerance and/or type 2 diabetes by OGTT) and insulin sensitivity (ISI), and its interplay with early-phase insulin secretion (i.e. disposition index [DI]) were analysed. Sample 2 (n=374) and sample 3 (n=394) were used to replicate the association with IGR and insulin sensitivity (by glucose clamp), respectively. Genotyping was performed by TaqMan allele discrimination. RESULTS: R84 carriers were at higher risk of IGR: OR for the additive model 1.54, p=0.004, and 1.63, p=0.027, in samples 1 and 2, respectively. In sample 1, both ISI (p=0.005) and DI (p=0.043) were progressively lower from QQ to QR and RR individuals. A 'triangulation approach' indicated that the association with IGR was mostly mediated by DI rather than by ISI changes (i.e. being the expected ORs 1.51 and 1.25, respectively). In sample 3, glucose disposal was 38.8+/-17.7, 33.8+/-14.4, and 31.6+/-13.3 micromol min(-1)kg(-1), p=0.022, in QQ, QR and RR individuals, respectively. CONCLUSIONS/INTERPRETATION: Our data confirm that the TRIB3 R84 variant affects glucose homeostasis and suggest this effect is due to an alteration of the interplay between insulin sensitivity and secretion.

An empirical index of insulin sensitivity from short IVGTT: validation against the minimal model and glucose clamp indices in patients with different clinical characteristics.

AIMS/HYPOTHESIS: Minimal model analysis for insulin sensitivity has been validated against the glucose clamp and is an accepted method for estimating insulin sensitivity from IVGTT. However minimal model analysis requires a 3 h test and relevant expertise to run the mathematical model. The aim of this study was to suggest a simple predictor of minimal model analysis index using only 1 h IVGTT. METHODS: We studied participants with different clinical characteristics who underwent 3 h regular (n = 336) or insulin-modified (n = 160) IVGTT, or 1 h IVGTT and euglycaemic-hyperinsulinaemic clamp (n = 247). Measures of insulin sensitivity were insulin sensitivity index estimated by minimal model analysis (S(I)) and the mean glucose infusion rate (clamp) (M). A calculated S(I) (CS(I)) predictor, CS(I) = Alpha X K(G)/(DeltaAUC(INS)/T), was suggested, based on the calculation of the rate of glucose disappearance K(G) and the suprabasal AUC of insulin concentration DeltaAUC(INS) over T = 40 min. For all the participants, alpha was assumed equal to the regression line slope between K(G)/(DeltaAUC(INS)/T) and S(I) in control participants. RESULTS: CS(I) and S(I) showed high correlation (R(2) = 0.68-0.96) and regression line slopes of approximately one in the majority of groups. CS(I) tended to overestimate S(I) in type 2 diabetic participants, but results were more reliable when CS(I) was computed with insulin-modified rather than regular IVGTT. CS(I) showed behaviours similar to S(I) as regards relationships with BMI, acute insulin response and sex. CS(I) showed good correlation with M (R(2) = 0.82). CONCLUSIONS/INTERPRETATION: A short test can achieve a good approximation of minimal model analysis and clamp insulin sensitivity. The importance of a method such as CS(I) is that it allows analysis of IVGTT datasets with samples limited to 1 h.

IRS1 G972R polymorphism and type 2 diabetes: a paradigm for the difficult ascertainment of the contribution to disease susceptibility of 'low-frequency-low-risk' variants.

AIMS/HYPOTHESIS: The aim of the study was to determine the association between IRS1 G972R polymorphism and type 2 diabetes; published data concerning this association have been conflicting. To obtain further insight into this topic, we performed a meta-analysis of all available case-control studies. METHODS: We performed a meta-analysis of 32 studies (12,076 cases and 11,285 controls). RESULTS: The relatively infrequent R972 variant was not significantly associated with type 2 diabetes (OR 1.09, 95% CI 0.96-1.23, p = 0.184 under a dominant model). Some evidence of heterogeneity was observed across studies (p = 0.1). In the 14 studies (9,713 individuals) in which the mean age at type 2 diabetes diagnosis was available, this variable explained 52% of the heterogeneity (p = 0.03). When these studies were subdivided into tertiles of mean age at diagnosis, the OR for diabetes was 1.48 (95% CI 1.17-1.87), 1.22 (95% CI 0.97-1.53) and 0.88 (95% CI 0.68-1.13) in the youngest, intermediate and oldest tertile, respectively (p = 0.0022 for trend of ORs). CONCLUSIONS/INTERPRETATION: Our findings illustrate the difficulties of ascertaining the contribution of 'low-frequency-low-risk' variants to type 2 diabetes susceptibility. In the specific context of the R972 variant, approximately 200,000 study individuals would be needed to have 80% power to identify a 9% increase in diabetes risk at a genome-wide significance level. Under these circumstances, a strategy aimed at improving outcome definition and decreasing its heterogeneity may critically enhance our ability to detect genetic effects, thereby decreasing the required sample size. Our data suggest that focusing on early-onset diabetes, which is characterised by a stronger genetic background, may be part of such a strategy.

Elevated one-hour post-load plasma glucose levels identifies subjects with normal glucose tolerance but early carotid atherosclerosis.

OBJECTIVE: To examine whether individuals with normal glucose tolerance (NGT), whose 1-h post-load plasma glucose is >or=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 >or=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 >or=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 >or=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.

Low plasma insulin-like growth factor-1 levels are associated with reduced insulin sensitivity and increased insulin secretion in nondiabetic subjects.

BACKGROUND AND AIM: Weight gain is associated with a decline in insulin sensitivity and a compensatory increase in insulin secretion. IGF-1 is a plausible candidate to explain these divergent phenomena. In this cross-sectional study, we analyzed the relationship between IGF-1 levels, insulin sensitivity and secretion in 110 nondiabetic subjects with a wide range of BMI to verify this hypothesis. METHODS AND RESULTS: Subjects underwent OGTT, IVGTT and euglycemic-hyperinsulinemic clamp. HOMA-beta, IVGTT-derived and OGTT-derived indexes for first-phase and second-phase insulin secretion were higher in obese as compared with overweight and normal-weight groups, while glucose disposal was lower. IGF-1 levels were negatively correlated with IVGTT-derived and OGTT-derived indexes first-phase and second-phase insulin secretion, and positively correlated with glucose disposal. These correlations were no longer significant after adjustment for BMI. In a multivariate analysis, the variables associated with glucose disposal were IGF-1, age, triglycerides, and 2-h post-load glucose accounting for 23.4% of its variation. When BMI was entered into the model, the variables associated with glucose disposal were triglycerides, 2-h post-load glucose and BMI accounting for 27.2% of variation. In a multivariate analysis, the only variable associated with IVGTT-derived first-phase and second-phase insulin secretion was IGF-1 accounting for 10.4% and 15.1% of variation, respectively. When BMI was entered into the model, it became the only variable associated with both first-phase and second-phase insulin secretion accounting for 25.7% and 37.6% of variation, respectively. CONCLUSION: These data suggest that progressive reduction in IGF-1 levels may be involved in obesity-related changes in both insulin sensitivity and secretion.