AIMS:To utilize the estimated glucose disposal rate (eGDR) index of insulin sensitivity, which is based on readily available clinical variables, namely, waist circumference, hypertension and glycated haemoglobin, to discriminate between metabolically healthy and unhealthy phenotypes, and to determine the prevalence of prediabetic conditions. METHODS:Non-diabetic individuals (n = 2201) were stratified into quartiles of insulin sensitivity based on eGDR index. Individuals in the upper quartiles of eGDR were defined as having metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW) or metabolically healthy obesity (MHO) according to their body mass index, while those in the lower quartiles were classified as having metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW) and metabolically unhealthy obesity (MUO), respectively. RESULTS:The frequency of impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and IFG + IGT status was comparable among the MHNW, MHOW and MHO groups, while it increased from those with MUNW status towards those with MUOW and MUO status. As compared with participants with MHNW, the odds ratio of having IFG, IGT, or IFG + IGT was significantly higher in participants with MUOW and MUO but not in those with MUNW, MHOW and MHO, respectively. CONCLUSIONS:A metabolically healthy phenotype is associated with lower frequency of IFG, IGT, and IFG + IGT status across all body weight categories.

Aims: Prior studies provided evidence that low-density lipoprotein (LDL)-cholesterol-lowering statins reduce cardiovascular events while conveying an increased risk of type 2 diabetes. The aim of this study was to investigate the association between LDL levels and both insulin sensitivity and insulin secretion in a cohort of 356 adult first-degree relatives of patients with type 2 diabetes. Methods: Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp and first-phase insulin secretion was measured by both intravenous glucose tolerance test (IVGTT) and OGTT. Results: LDL-cholesterol levels were not independently associated with insulin-stimulated glucose disposal. After adjusting for several potential confounders, LDL-cholesterol concentration exhibited a positive independent association with acute insulin response (AIR) during IVGTT and with the OGTT derived Stumvoll first-phase insulin secretion index. When insulin release was adjusted for the underlying degree of insulin sensitivity, using the disposition index (AIR x insulin-stimulated glucose disposal), beta-cell function was significantly asso-ciated with LDL-cholesterol levels, even after further adjusting for several potential confounders. Conclusions: The present results suggest that LDL cholesterol is a positive modulator of insulin secretion. The deterioration in glycemic control observed during treatment with statins might thus be explained by an impairment in insulin secretion due to the cholesterol-lowering effect of statins.

Aims: To assess sex-related differences in whole-body insulin sensitivity and insulin secretion in a group of Caucasian subjects with varying degrees of glucose tolerance. Methods: Sex-related differences in insulin sensitivity using the hyperinsulinemic-euglycemic clamp technique and insulin secretion using validated indexes obtained during an oral glucose tolerance test were examined among 570 non-diabetic offspring individuals having only one parent with type 2 diabetes. Participants were classified as having with NGT, isolated impaired fasting glucose (IFG), isolated impaired glucose tolerance (IGT) and combined IFG/IGT. Results: Isolated IFG, isolated IGT, and combined IFG/IGT women exhibited greater relative differences in BMI, waist circumference, and insulin-stimulated glucose disposal than their male counterparts. Formal tests for glucose tolerance status x sex interaction were statistically significant for BMI (P = 0.05) waist circumference (P = 0.04), and insulin-stimulated glucose disposal (P = 0.01) suggesting a sex-specific association. By contrast, tests for glucose tolerance status x sex interaction regarding both insulinogenic and disposition indexes were not significant. Conclusions: This study suggests that deterioration of glucose homeostasis in women is associated with a greater fat accumulation and worsening in insulin sensitivity as compared with men.

Aim: Individuals with high 1-hour post-load glucose (1-h PG > 155 mg/dl; 8.6 mmol/l) during an oral glucose tolerance test are at increased risk of type 2 diabetes (T2D) and cardiovascular complications, hepatic steatosis, and mortality. However, the clinical relevance of 1-h PG for the severity of hepatic fibrosis risk remains undefined. Methods: Cross-sectional data of the CATAMERI study (n = 2335) were analyzed. Participants underwent anthropometric measurements, liver enzyme determinations, cardiometabolic profiling, and a 75-gram oral glucose tolerance test, including fasting, 1-h and 2-h PG determinations and measurement of FIB-4 score to assess degree of hepatic fibrosis. Multivariable logistic regression analysis was performed to evaluate risk of advanced hepatic fibrosis with worsening glycemic status. Results: We stratified the study group into 6 categories based on glycemic status: normal glucose tolerance (NGT) 1h-PG Low, NGT 1h-PG High, iIFG 1h-PG Low, iIFG 1h-PG High, IGT, and newly detected T2D. Anthropometric and cardiometabolic profiles worsened gradually with glycemic status. Moreover, compared to NGT-1h-PG Low group, worsening glycemic status was significantly associated with the severity of fibrosis, independent of other significant clinical risk factors. Conclusions: 1-PG is a valuable tool for stratifying subjects with NGT or IFG at heightened risk of hepatic fibrosis requiring further evaluation with elastography.

Aims: To characterize the prevalence of NAFLD among subjects with NGT, prediabetes and type 2 diabetes (T2DM) by sex in adults with one or more cardio-metabolic risk factors, and to assess whether cardio-metabolic factors explained sex-related differences in NAFLD prevalence. Methods: The study sample encompasses 742 individuals with NGT, 553 with prediabetes, and 431 with T2DM. Results: Women with prediabetes and T2DM exhibited greater relative differences in waist circumference, HOMA-IR, hsCRP, and lipid profile than prediabetic and diabetic men when compared with their NGT counterparts. Formal tests for glucose tolerance status x sex interaction were statistically significant for waist circumference (P=0.008), HOMA-IR (P=0.03), total cholesterol (P=0.003), LDL (P=0.001), HDL (P=0.006), triglycerides (P<0.0001), and hsCRP (P<0.05). In a logistic regression analysis, prediabetic and diabetic women exhibited a higher OR for NAFLD than their male counterparts with test for glucose tolerance status x sex interaction being statistically significant. Conclusions: Prediabetic and diabetic women have higher OR of having NAFLD than men. Deterioration of glucose homeostasis in women is associated with a greater worsening in metabolic risk factors than men, which may explain the stronger impact of prediabetes and T2DM on NAFLD in women.

Experimental evidence indicates that high‐density lipoprotein (HDL) may stimulate glucose uptake and improve β‐cell function. The aim of this study was to evaluate whether lower levels of HDL may affect the risk to develop type 2 diabetes.

In our institution, a multi-disciplinary team consisting of endoscopists, surgeons, nutritionists, and pathologists is involved in the management of inflammatory bowel diseases. Over the last 18 years, data have been collected in a dedicated database. We retrospectively reviewed our activity to analyse whether the biological agents introduction influenced the treatment strategies in Crohn’s disease (CD) patients who required a second surgery. We retrospectively reviewed our database from 2000 to 2012 and selected patients with at least 6-year follow-up who underwent major surgery almost once in their life, including those previously treated in other centres. These patients were divided into four groups according to the medical treatment administered after surgery: patients treated with biologic agents (anti-TNFa) (Group A), with immunosuppressive drugs (azathioprine) (Group B), with immunosuppressive and biologic therapy (Group C) and with 5-aminosalicylic (5-ASA) (Group D). The difference between groups were calculated with χ2 test. From 2000 to 2012, 206 patients with CD referred to our hospital. Among them, 137 patients underwent major surgery at least once in their life. After surgery, 23 patients were treated with biologic agents (Group A), 39 with immunosuppressive drugs (Group B), 51 with immunosuppressive and biologic therapy (Group C) and 24 with 5-ASA (Group D). Overall, 31 patients surgically recurred even though the medical therapy. Patients’ surgical recurrence data are shown in Table 1 according to the pre-operative medical treatment. The reasons for re-operations are summarised in Table 2. Surgical recurrence data according to the medical treatment at the time of the re-operation. Surgical recurrence data according to the medical treatment at the time of the re-operation. Reasons of reoperation among medical treatment groups. Reasons of reoperation among medical treatment groups. According to our data, none of the currently available drugs can significantly reduce alone the re-operation rate for CD. The combined use of immunosuppressive and biologic drugs does not seem to be the convincing strategy to delay surgical recurrence in Crohn’s disease.

Introduction:Insulin resistance plays a crucial role in the pathogenesis of type 2 diabetes and cardiovascular disease. The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio, visceral adiposity index (VAI), lipid accumulation product (LAP) and triglycerides × fasting glucose (TyG) index are surrogate measures of insulin sensitivity based on anthropometric and/or biochemical parameters routinely collected in clinical practice. Herein, we compared the relationships of these four surrogate indexes with insulin sensitivity assessed by the gold standard euglycemic hyperinsulinemic clamp technique, and subclinical vascular damage.Research design and methods:631 subjects with different degrees of glucose tolerance underwent euglycemic hyperinsulinemic clamp. The surrogate TG/HDL-C ratio, VAI, LAP and TyG indexes were computed. Pulse pressure and carotid intima-media thickness (IMT) were measured as indicators of subclinical vascular damage.Results:All the four surrogate indexes showed a significant correlation with insulin-stimulated glucose disposal in the whole study population. However, only LAP index had a significant association with insulin sensitivity across the different glucose tolerance groups. LAP index showed the highest area under the receiver operating characteristic curve (0.728) to detect individuals with insulin resistance defined as the bottom quartile of insulin-stimulated glucose disposal, followed by TG/HDL-C ratio (0.693), TyG index (0.688) and VAI (0.688). A significant association was found between the four indexes of insulin sensitivity and pulse pressure and IMT. All the four indexes have a similar ability to detect individuals with vascular atherosclerosis defined by IMT>0.9 mm. Conversely, LAP index had the greatest ability to recognize individuals with increased vascular stiffness defined by pulse pressure ≥60 mm Hg.Conclusion:Among the surrogate TG/HDL-C ratio, VAI, LAP and TyG indexes of insulin sensitivity, LAP index showed a significant association with insulin-stimulated glucose disposal across the different glucose tolerance categories and the highest ability to detect insulin resistance and subclinical vascular damage.

Previous studies suggested that the IGF-1/IGF-1 receptor signaling pathway may contribute to regulate uric acid levels. To confirm this hypothesis, we assessed the effects of the IGF-1-raising genetic variant rs35767 on urate levels in serum and urine, and we investigated IGF-1 ability to modulate the expression of transporters involved in reabsorption and secretion of uric acid in the kidney. The study population included 2794 adult Whites. 24-hour urinary uric acid concentration was available for 229 subjects. rs35767 polymorphism was screened using TaqMan genotyping assays. HEK293 (human embryonic kidney-293) cell line was treated with IGF-1 (1, 5, 10, 50 nM) for 24-hours, and differences in the expression of urate transporters were evaluated via Western Blot and real time rtPCR. Individuals carrying the IGF-1-raising allele (rs35767 T) exhibited significantly lower levels of serum urate according to both additive and recessive models, after correction for gender, age, BMI, glucose tolerance, glomerular filtration rate, and anti-hypertensive treatment. TT genotype carriers displayed higher uricosuria than C allele carriers did, after adjusting for confounders. Exposure of HEK293 cells to IGF-1 resulted in a dose-dependent increase of uric acid transporters deputed to uric acid excretion (MRP4, NPT1 and BCRP), and reduction of GLUT9 expression, the major mediator of uric acid reabsorption, both at mRNA and protein level. We observed a significant association between the functional polymorphism rs35767 near IGF1 with serum urate concentrations and we provide a mechanistic explanation supporting a causal role for IGF-1 in the regulation of uric acid homeostasis.

Context Recently, a value of 1-hour postload glucose concentration (1-h-PG) ≥155 mg/dL (8.6 mmol/L) in individuals with normal glucose tolerance (NGT) has been found to be associated with an increased risk for future type 2 diabetes mellitus (T2DM). In this review, we analyze the implication of 1-h-PG determination in prediction of T2DM and cardiovascular disease. Design A literature search was performed using MEDLINE. We included all English studies published up to February 2018 in peer-reviewed journals that examined the relationship between 1-h-PG and diabetes, cardiometabolic alterations, organ damage, and cardiovascular disease. Results Several longitudinal studies have consistently shown that 1-h-PG ≥155 mg/dL can recognize individuals at increased risk for future T2DM among subjects with NGT. Additionally, we describe the pathophysiological abnormalities associated with 1-h-PG ≥155 mg/dL including impaired insulin sensitivity, β-cell dysfunction, and increased glucose intestinal absorption, which are known to be involved in T2DM pathogenesis. Importantly, numerous studies have demonstrated that a value of 1-h-PG ≥155 mg/dL in individuals with NGT is not only linked to an increased risk for future T2DM, but also able to identify those having a worse cardiovascular phenotype and an increased risk of adverse cardiovascular outcomes. Conclusions Although 1-h-PG determination is not currently recommended by the American Diabetes Association for identifying high-risk individuals, the available evidence indicates that a value of 1-h-PG ≥155 mg/dL may be a useful tool to recognize, among subjects with NGT, those at increased risk of T2DM and cardiovascular disease.

Hemoglobin glycation index (HGI), calculated as the difference between the observed value of HbA1 and the predicted HbA1c based on plasma glucose concentration, is a measure of the individual tendency toward non-enzymatic hemoglobin glycation which has been found to be positively associated with nephropathy in subjects with diabetes. In this cross-sectional study we aimed to evaluate whether higher HGI levels are associated with impaired kidney function also among nondiabetic individuals. The study group comprised 1505 White nondiabetic individuals stratified in quartiles according to HGI levels. Estimated glomerular filtration rate (eGFR) was calculated by using the MDRD equation. Individuals in the intermediate and high HGI groups exhibited a worse metabolic phenotype with increased levels of visceral obesity, total cholesterol, triglycerides, inflammatory biomarkers such as hsCRP and white blood cells count and lower values of HDL and insulin sensitivity assessed by Matsuda index in comparison to the lowest quartile of HGI. Subjects in the intermediate and high HGI groups displayed a graded decrease of eGFR levels in comparison with the lowest quartile of HGI. In a logistic regression analysis individuals in the highest quartile of HGI exhibited a significantly 3.6-fold increased risk of having chronic kidney disease (95% CI: 1.13-11.24, P = 0.03) and a significantly 1.6-fold increased risk of having a mildly reduced kidney function (95% CI: 1.19-2.28, P = 0.003) in comparison to individuals in the lowest HGI group. In conclusion HGI may be a useful tool to identify nondiabetic individuals with an increased risk of having kidney dysfunction.

Hemoglobin glycation index (HGI), defined as the difference between the observed HbA1c value and the value of HbA1c predicted from plasma glucose levels, represents a measure of the degree of non-enzymatic glycation of hemoglobin and it has been found to be positively associated with micro- and macro-vascular complications in subjects with type 2 diabetes. To investigate the pathophysiological abnormalities responsible for the increased cardiovascular risk of patients with higher HGI, we evaluated the association of HGI with cardio-metabolic characteristics in nondiabetic offspring of type 2 diabetic individuals. Insulin sensitivity, measured by a hyperinsulinemic-euglycemic clamp, cardio-metabolic risk factors including lipid profile, uric acid and inflammatory factors, and ultrasound measurement of carotid intima-media thickness (IMT) were assessed in 387 nondiabetic individuals. Participants were stratified in tertiles according to HGI (high, moderate and low). As compared with subjects with low HGI, those with high HGI displayed an unfavorable cardio-metabolic risk profile having significantly higher values of BMI, waist circumference, triglycerides, uric acid, fasting insulin, inflammatory markers, such as high sensitivity C reactive protein, erythrocytes sedimentation rate, complement C3, fibrinogen, and white blood cell count, and carotid IMT, and lower HDL and insulin-stimulated glucose disposal. In a linear regression analysis model including several atherosclerotic risk factors such as gender, age, BMI, inflammatory factors, lipid profile, insulin-stimulated glucose disposal, fasting insulin, uric acid, and blood pressure, HGI was the major predictor of IMT (β = 0.35; P = 0.001). In a logistic regression analysis adjusted for confounders, individuals with high HGI showed a 2.7-fold increased risk of vascular atherosclerosis (OR 2.72, 95%CI 1.01-7.37) as compared with subjects with low HGI. The present findings support the notion that HGI may be a useful tool to identify a subset of nondiabetic individuals conceivably harboring a higher risk of cardiovascular disease.

Objective— Serum uric acid (UA) has been associated with increased risk of cardiovascular and metabolic diseases. However, the causal mechanisms linking elevated UA levels to cardio-metabolic diseases are still unsettled. One potential explanation for how UA might contribute to cardio-metabolic disease might be its ability to induce systemic inflammation. Approach and Results— Herein, we report a positive relationship between serum UA and acute-phase reactants, such as high-sensitivity C-reactive protein, fibrinogen, ferritin, complement C3, and erythrocyte sedimentation rate, in a cohort of 2731 nondiabetic adults. The relationship remains significant after adjustment for several confounders, including age, sex, adiposity, anti-hypertensive treatments or diuretics use. To confirm the existence of a causal relationship, we examined the effect of UA on the expression of inflammatory biomarkers in human hepatoma HepG2 cells and characterized the signaling pathway by which UA acts. We show that UA stimulates the expression of C-reactive protein, fibrinogen, ferritin, and complement C3 in a dose-dependent fashion. The proinflammatory effects of UA were abrogated by benzbromarone, a specific inhibitor of UA transporters. Exposure of cells to UA resulted in activation of the IκB kinase/IκBα/NF-κB signaling pathway that was attenuated by benzbromarone. The effect of UA was completely blocked by the antioxidant N -acetylcysteine. Conclusions— These in vivo and in vitro data suggest that hyperuricemia might induce the expression of hepatic inflammatory molecules by activating the proinflammatory NF-κB signaling cascade. Because inflammation has an important pathogenetic role in metabolic and cardiovascular disease, our study may help understanding the mechanism by which hyperuricemia may contribute to organ damage.

In vitro and in vivo studies suggest that IGF-1 has a role in erythropoiesis. There is evidence that the rs35767 C/T polymorphism near IGF1 is associated with plasma IGF-1 levels. We investigated the effect of this polymorphism on hemoglobin (Hb) concentration and anemia. The study group comprised 3286 adult Whites. The rs35767 polymorphism was screened using a TaqMan allelic discrimination assay. The rs35767 polymorphism was not associated with age, gender, BMI, waist circumference, smoking, blood pressure, plasma glucose, HbA1c, type 2 diabetes, HOMA-IR, hsCRP, eGFR, and lipid profile. Erythrocyte sedimentation rate (ESR), fibrinogen, and fasting insulin levels were significantly lower in TT genotype carriers compared with C allele carriers. Hb concentration was significantly higher in carriers of the TT genotype compared with C allele carriers, and a lower proportion of TT carriers had anemia. As compared with TT genotype carriers, those bearing the CC genotype had a 2.4-fold higher risk of anemia (OR 2.40, 95%CI 1.19-4.82), and those with the CT genotype had a 2.0-fold higher risk of anemia (OR 2.06, 95%CI 1.04-4.11). The association remained significant when fasting insulin, eGFR, smoking, diabetes, ACE inhibitors, sartans or diuretics treatments, use of metformin and pioglitazone were added to the model, but its independence was not retained after inclusion of fibrinogen and ESR values into the model. In conclusion, rs35767 TT allele carriers exhibited significantly higher concentrations of Hb, and lower risk of anemia compared with C allele carriers supporting the idea that IGF-1 plays a role in erythropoiesis homeostasis.

AIMS:Hemoglobin glycation index (HGI), which is the difference between the observed value of HbA1 and the predicted HbA1c based on plasma glucose levels, represents a measure of the degree of non-enzymatic glycation of hemoglobin and it has been found to be positively associated with diabetic complications. Herein we investigated whether HGI is associated with hepatic steatosis and related biomarkers in subjects without diabetes. METHODS:1120 White individuals without diabetes were stratified in quartiles according to HGI levels. Hepatic steatosis was diagnosed by ultrasonography. RESULTS:As compared with subjects in the lowest quartile of HGI those in the intermediate and high HGI groups displayed an unfavorable cardio-metabolic risk profile having significantly higher values of body mass index (BMI), waist circumference, % fat mass, total cholesterol, triglycerides, inflammatory markers such as high sensitivity C reactive protein, erythrocytes sedimentation rate, complement C3, platelets and white blood cell count, hepatic insulin resistance assessed by the liver IR index and lower concentrations of high-density lipoprotein. HGI was positively associated with the biomarker of liver damage alanine aminotransferase, and fatty liver index, an indicator of hepatic steatosis. In a logistic regression analysis adjusted for age, gender and BMI individuals in the highest quartile of HGI exhibited a 1.6-fold increased odd of having hepatic steatosis (95% CI: 1.03-2.41; p=0.03) as compared with subjects in the lowest quartile of HGI. CONCLUSIONS:Higher levels of HGI may identify subjects without diabetes at increased risk of having hepatic steatosis.

OBJECTIVE Hair loss generates severe psychosocial implications. To date, exploring the prognostic factors of possible clinical benefit of autologous blood concentrate platelet rich plasma (PRP) was failed. The aim of our pilot study was to explore the correlation between the individual inflammation genetic profile and PRP efficacy in the treatment of hair follicle regeneration. PATIENTS AND METHODS 41 volunteers (25 men, 16 women) took part in this retrospective study. All the patients were scheduled for 4 sessions of PRP application with intervals of 40-60 days. All the patients were checked up at 6 weekly intervals for 6 months and, then, at the end of the first year. A panel of 5 polymorphisms on 4 genes (IL-1a, IL-1b, IL-6, and IL-10) implicated in the individual genetic inflammation profile were performed. RESULTS A significant increase rate in hair density was noticed after the third month of treatment in 32/41 (78%) of the subjects. We found an interesting association between the pro-inflammatory cytokine IL-1α polymorphism C>A (rs17561) and responders to PRP treatment. The cases carrying C/C genotype (coding for Ser114) were 21 (66%) in responders and only 2 (22%) in non-responders (p<0.05). In addition, about IL-1a, the frequency of G/G genotype in responder patients was over two times lower in responder (31%) than in non-responder patients (78%). CONCLUSIONS Our pilot study demonstrated a correlation between the individual genetic inflammatory profile and the efficacy of the PRP treatment in males. On the contrary, in females, it showed a negative correlation. IL-1a could be used as a prognostic value for PRP efficacy. Also, these results provide preliminary evidence that may encourage the design of controlled clinical trials to properly test this modus operandi on a large number of subjects.

AIM:It has been suggested that glucose levels ≥155 mg/dl at 1-h during an oral glucose tolerance test (OGTT) may predict development of type 2 diabetes and cardiovascular events among adults with normal glucose tolerance (NGT 1 h-high). Studies showed a link between increased blood viscosity and type 2 diabetes. However, whether blood viscosity is associated with dysglycemic conditions such as NGT 1 h-high, impaired glucose tolerance (IGT) or impaired fasting glucose (IFG) is unsettled. METHODS:1723 non-diabetic adults underwent biochemical evaluation and OGTT. A validated formula based on hematocrit and total plasma proteins was employed to estimate whole blood viscosity. Subjects were categorized into NGT with 1 h glucose <155 mg/dL (NGT-1 h-low), NGT-1 h-high, IFG and/or IGT. RESULTS:Hematocrit and blood viscosity values appeared significantly higher in individuals with NGT 1 h-high, IFG and/or IGT as compared to NGT 1 h-low subjects. Blood viscosity was significantly correlated with age, waist circumference, blood pressure, HbA1c, fasting, 1- and 2-h post-challenge insulin levels, total cholesterol and low-density lipoprotein, triglycerides, fibrinogen, white blood cell, and inversely correlated with high-density lipoprotein and insulin sensitivity. Of the four glycemic parameters, 1-h post-challenge glucose showed the strongest correlation with blood viscosity (β = 0.158, P < 0.0001) in a multivariate regression analysis model including several atherosclerosis risk factors. CONCLUSIONS:Our results demonstrate a positive relationship between blood viscosity and 1-h post-challenge plasma glucose. They also suggest that a subgroup of NGT individuals with 1-h post-challenge plasma >155 mg/dl have increased blood viscosity comparable to that observed in subjects with IFG and/or IGT.

Context: Subjects with normal glucose tolerance (NGT) but 1-h postload glucose >= 155 mg/dL (NGT-1h-high) exhibit an intermediate cardiometabolic risk profile between individuals with NGT and impaired glucose tolerance (IGT).Objective: This study aimed to evaluate whether NGT-1h-high subjects have different cardiometabolic characteristics and an increased risk of type 2 diabetes compared with individuals with isolated impaired fasting glucose (IFG).Setting, Design, and Patients: Across-sectional analysis was performed on 595 nondiabetic subjects who underwent an oral glucose tolerance test and an euglycemic hyperinsulinemic clamp in an ambulatory care setting. In addition, a longitudinal analysis was performed on 392 individuals, who were reexamined after a followup of 5.2 +/- 0.9 y.Main Outcome Measures: Insulin sensitivity, beta-cell function, and risk of developing diabetes were measured.Results: Subjects with NGT-1h-high have a significant reduction of peripheral insulin sensitivity and beta-cell function, assessed by the disposition index, compared with either 1-h postload glucose < 155 mg/dL (NGT-1h-low) or IFG individuals, but not compared with IGT. Among the 392 subjects studied in the longitudinal analysis the incidence rate of type 2 diabetes over the follow-up period was 2.9, 16.7, 12.5, and 31.4% for subjects with NGT-1h-low, NGT-1h-high, IFG, and IGT, respectively. In a Cox proportional hazard regression analysis the risk of developing diabetes for NGT-1h-high subjects was 4.02 (95% confidence interval [CI] 1.06-15.26); an even higher risk (6.67; 95% CI, 2.09-21.24) was observed in subjects with IGT, but not in the isolated IFG group (1.91; 95% CI, 0.44-8.29).Conclusions: NGT-1h-high subjects exhibit a higher risk of developing diabetes than those with IFG or NGT-1h-low, likely due to decreased insulin sensitivity and beta-cell function.