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Aims: The International Diabetes Federation (IDF) has recently recommended determination of 1-hour plasma glucose (1-hPG) during an oral glucose tolerance test (OGTT) to diagnose intermediate hyperglycemia (IH) and type 2 diabetes (T2DM). Herein, we investigated the cardiometabolic characteristics of individuals with IH and T2DM according to IDF criteria., Methods: We studied 3086 individuals stratified on the basis of fasting, 1-hPG and 2-hPG in four groups: 1) normal glucose tolerance (NGT), 2) isolated impaired fasting glucose (iIFG,), 3) IH (fasting glucose < 126 mg/dL, 1-hPG 155-208 mg/dL, and/or 2-hPG 140-199 mg/dL, and 4) newly diagnosed T2DM (fasting glucose, 1-hPG and/or 2-hPG≥126 mg/dL, 209 mg/dL and 200 mg/dL, respectively)., Results: Individuals with IH and T2DM exhibited higher adiposity, blood pressure, uric acid, a worse lipid and inflammatory profile and a progressive reduction in Matsuda index of insulin sensitivity, insulinogenic index, and disposition index as compared to the NGT group. Moreover, individuals with IH and T2DM exhibited lower Matsuda, insulinogenic, and disposition indexes as compared to the iIFG group., Conclusions: 1-h PG-based criteria for diagnosis of IH and diabetes identify individuals having an unfavorable cardiometabolic risk profile with a progressive reduction in insulin sensitivity associated with impaired β cell function., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Diabetic cardiomyopathy (DbCM) is characterized by restrictive pattern and consistent risk of overt heart failure. We here focused osteopontin (OPN), which was tested independently associated with left ventricular diastolic dysfunction (LVDD). Overall, OPN increased with DbCM severity according with the presence of left atrial dilatation, LV hypertrophy and LVDD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [LL and GGC are coinventors on the International Patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischemia-reperfusion injury to the central nervous system. GGC is a consultant to Sovida solutions limited.]., (Copyright © 2023. Published by Elsevier B.V.)

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 × insulin-stimulated glucose disposal), β-cell function was significantly associated 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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 × 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 × 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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 × 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 × 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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

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 a75-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 stratifiedthe 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., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: Subjects with elevated 1 h post-load glucose concentrations (1hPG) exhibit increased risk of non-alcoholic fatty liver disease (NAFLD) and duodenal sodium/glucose co-transporter 1 (SGLT-1) levels. Herein, we evaluate whether higher SGLT-1 duodenal levels are associated with NAFLD and increased risk of advance liver fibrosis., Methods: SGLT-1 levels were assessed on duodenal mucosa in 52 individuals subdivided into two groups according to ultrasonography-defined presence of NAFLD. Intracellular triglycerides levels and activation of endoplasmic reticulum (ER) stress were evaluated in human hepatocytes exposed to high-glucose concentration (HG)., Results: Individuals with NAFLD exhibited higher duodenal SGLT-1 abundance along with raised 1hPG, as compared to those without NAFLD. The mediation analysis showed that augmented duodenal SGLT-1 levels were a predictor of NAFLD, and the link between increased duodenal SGLT-1 content and NAFLD risk was mediated by augmented 1hPG. Amongst participants with NAFLD, those with intermediate/high probability of advance liver fibrosis, estimated by NAFLD fibrosis score, exhibited higher duodenal SGLT-1 abundance and 1hPG levels as compared to the low probability group. Hepatocytes exposed to HG showed increased triglycerides accumulation and an up-regulation of ER stress pathway., Conclusions: Increased duodenal SGLT-1 abundance and the related early post-prandial hyperglycemia are associated with NAFLD and advance liver fibrosis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: Individuals with HbA1c-defined prediabetes (HbA1c 5.7-6.4%) and 1-hour post-load plasma glucose (1hPG) ≥ 155 mg/dl have an increased risk to develop type 2 diabetes (T2DM). T2DM is associated with a higher intestinal expression of sodium/glucose co-transporter 1 (SGLT-1) and glucose transporter 2 (GLUT-2). It is currently unsettled whether HbA1c-defined dysglycemic conditions combined to 1hPG ≥ 155 mg/dl are associated with changes in SGLT-1 and GLUT-2 duodenal abundance., Methods: SGLT-1 and GLUT-2 protein levels were assessed by western blot on duodenal mucosa biopsies of 57 individuals underwent an upper gastrointestinal endoscopy., Results: Compared with the normal group (HbA1c < 5.7%), individuals with HbA1c-defined pre-diabetes and diabetes exhibit no significant change in duodenal SGLT-1 abundance. Conversely, duodenal GLUT-2 levels were progressively increased in subjects with prediabetes and diabetes. Stratifying participants according to HbA1c and 1hPG we found that amongst subjects with HbA1c-defined normal or prediabetes condition those having 1hPG ≥ 155 mg/dl displayed higher duodenal levels of SGLT-1 as compared to their counterparts with 1hPG < 155 mg/dl; in contrast to GLUT-2 levels, which were similar between normal and with prediabetes subjects, regardless of 1hPG value., Conclusion: A value of 1hPG ≥ 155 mg/dl may identify a subset of individuals within HbA1c-defined glycemic categories having a higher duodenal abundance of SGLT-1., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Prediabetes (intermediate hyperglycemia) consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) detected by a standardized 75-gram oral glucose tolerance test (OGTT). Individuals with isolated IGT or combined IFG and IGT have increased risk for developing type 2 diabetes (T2D) and cardiovascular disease (CVD). Diagnosing prediabetes early and accurately is critical in order to refer high-risk individuals for intensive lifestyle modification. However, there is currently no international consensus for diagnosing prediabetes with HbA1c or glucose measurements based upon American Diabetes Association (ADA) and the World Health Organization (WHO) criteria that identify different populations at risk for progressing to diabetes. Various caveats affecting the accuracy of interpreting the HbA1c including genetics complicate this further. This review describes established methods for detecting glucose disorders based upon glucose and HbA1c parameters as well as novel approaches including the 1-hour plasma glucose (1-h PG), glucose challenge test (GCT), shape of the glucose curve, genetics, continuous glucose monitoring (CGM), measures of insulin secretion and sensitivity, metabolomics, and ancillary tools such as fructosamine, glycated albumin (GA), 1,5- anhydroglucitol (1,5-AG). Of the approaches considered, the 1-h PG has considerable potential as a biomarker for detecting glucose disorders if confirmed by additional data including health economic analysis. Whether the 1-h OGTT is superior to genetics and omics in providing greater precision for individualized treatment requires further investigation. These methods will need to demonstrate substantially superiority to simpler tools for detecting glucose disorders to justify their cost and complexity., Competing Interests: Declaration of Competing Interest We declare no competing interests., (Published by Elsevier B.V.)

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)