HDL cholesterol is an independent predictor of ß-cell function decline and incident type 2 diabetes: A longitudinal study.

BACKGROUND: Experimental evidence indicates that high-density lipoprotein (HDL) may stimulate glucose uptake and improve ß-cell function. The aim of this study was to evaluate whether lower levels of HDL may affect the risk to develop type 2 diabetes. METHODS: Incident rate of type 2 diabetes and changes in insulin sensitivity and ß-cell function over 5.5-year follow-up were examined in 670 non-diabetic subjects stratified in tertiles according to basal HDL levels. RESULTS: As compared to the highest tertile of HDL, individuals with lower levels of HDL have an increased risk to develop type 2 diabetes independently from several cardiometabolic risk factors (odds ratio: 2.88, 95% confidence interval: 1.05-7.91), and exhibited a greater deterioration of ß-cell function, estimated by the disposition index, over 5.5-year follow-up. Conversely, changes in Matsuda index of insulin sensitivity over the follow-up were not significantly different amongst the three HDL groups. In a multivariable regression analysis model including age, sex, waist circumference, triglycerides, total cholesterol, C-reactive protein, fasting and 2-hour post-load glucose, family history of type 2 diabetes and smoking habit, HDL concentration at baseline was an independent predictor of ß-cell function decline over the follow-up (ß = .30, P = .0001). Mediation analysis showed that the association between lower HDL levels at baseline and increased risk of incident diabetes was mediated by ß-cell function deterioration during the follow-up (t = -3.32, P = .001). CONCLUSIONS: Subjects with lower levels of HDL have an increased risk to develop type 2 diabetes likely due to a greater ß-cell function decline over time.

Analysis of age-dependent gene-expression in human tissues for studying diabetes comorbidities.

The study of the relationship between type 2 diabetes mellitus (T2DM) disease and other pathologies (comorbidities), together with patient age variation, poses a challenge for medical research. There is evidence that patients affected by T2DM are more likely to develop comorbidities as they grow older. Variation of gene expression can be correlated to changes in T2DM comorbidities insurgence and progression. Understanding gene expression changes requires the analysis of large heterogeneous data at different scales as well as the integration of different data sources into network medicine models. Hence, we designed a framework to shed light on uncertainties related to age effects and comorbidity by integrating existing data sources with novel algorithms. The framework is based on integrating and analysing existing data sources under the hypothesis that changes in the basal expression of genes may be responsible for the higher prevalence of comorbidities in older patients. Using the proposed framework, we selected genes related to comorbidities from existing databases, and then analysed their expression with age at the tissues level. We found a set of genes that changes significantly in certain specific tissues over time. We also reconstructed the associated protein interaction networks and the related pathways for each tissue. Using this mechanistic framework, we detected interesting pathways related to T2DM whose genes change their expression with age. We also found many pathways related to insulin regulation and brain activities, which can be used to develop specific therapies. To the best of our knowledge, this is the first study that analyses such genes at the tissue level together with age variations.

Exploiting the molecular basis of age and gender differences in outcomes of SARS-CoV-2 infections.

Motivation: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease, 2019; COVID-19) is associated with adverse outcomes in patients. It has been observed that lethality seems to be related to the age of patients. While ageing has been extensively demonstrated to be accompanied by some modifications at the gene expression level, a possible link with COVID-19 manifestation still need to be investigated at the molecular level. Objectives: This study aims to shed out light on a possible link between the increased COVID-19 lethality and the molecular changes that occur in elderly people. Methods: We considered public datasets of ageing-related genes and their expression at the tissue level. We selected human proteins interacting with viral ones that are known to be related to the ageing process. Finally, we investigated changes in the expression level of coding genes at the tissue, gender and age level. Results: We observed a significant intersection between some SARS-CoV-2 interactors and ageing-related genes, suggesting that those genes are particularly affected by COVID-19 infection. Our analysis evidenced that virus infection particularly involves ageing molecular mechanisms centred around proteins EEF2, NPM1, HMGA1, HMGA2, APEX1, CHEK1, PRKDC, and GPX4. We found that HMGA1 and NPM1 have different expressions in the lung of males, while HMGA1, APEX1, CHEK1, EEF2, and NPM1 present changes in expression in males due to ageing effects. Conclusion: Our study generated a mechanistic framework to clarify the correlation between COVID-19 incidence in elderly patients and molecular mechanisms of ageing. We also provide testable hypotheses for future investigation and pharmacological solutions tailored to specific age ranges.

Reduction in Global Myocardial Glucose Metabolism in Subjects With 1-Hour Postload Hyperglycemia and Impaired Glucose Tolerance.

OBJECTIVE: Impaired insulin-stimulated myocardial glucose uptake has occurred in patients with type 2 diabetes with or without coronary artery disease. Whether cardiac insulin resistance is present remains uncertain in subjects at risk for type 2 diabetes, such as individuals with impaired glucose tolerance (IGT) or those with normal glucose tolerance (NGT) and 1-h postload glucose ≥155 mg/dL during an oral glucose tolerance test (NGT 1-h high). This issue was examined in this study. RESEARCH DESIGN AND METHODS: The myocardial metabolic rate of glucose (MRGlu) was measured by using dynamic 18F-fluorodeoxyglucose positron emission tomography combined with a euglycemic-hyperinsulinemic clamp in 30 volunteers without coronary artery disease. Three groups were studied: 1) those with 1-h postload glucose <155 mg/dL (NGT 1-h low) (n = 10), 2) those with NGT 1-h high (n = 10), 3) and those with IGT (n = 10). RESULTS: After adjusting for age, sex, and BMI, both subjects with NGT 1-h high (23.7 ± 6.4 mmol/min/100 mg; P = 0.024) and those with IGT (16.4 ± 6.0 mmol/min/100 mg; P < 0.0001) exhibited a significant reduction in global myocardial MRGlu; this value was 32.8 ± 9.7 mmol/min/100 mg in subjects with NGT 1-h low. Univariate correlations showed that MRGlu was positively correlated with insulin-stimulated whole-body glucose disposal (r = 0.441; P = 0.019) and negatively correlated with 1-h (r = -0.422; P = 0.025) and 2-h (r = -0.374; P = 0.05) postload glucose levels, but not with fasting glucose. CONCLUSIONS: This study shows that myocardial insulin resistance is an early defect that is already detectable in individuals with dysglycemic conditions associated with an increased risk of type 2 diabetes, such as IGT and NGT 1-h high.

Individuals With Prediabetes Display Different Age-Related Pathophysiological Characteristics.

CONTEXT: Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) are highly pathophysiologic heterogeneous prediabetes conditions that can occur in all age groups, from youth to elderly people. OBJECTIVE: We evaluated whether distinct age-related phenotypes exist among individuals with IFG or IGT. RESEARCH DESIGN: 479 young (aged 18 to 35 years), 699 adult (45 to 55 years) and 240 older (≥65 years) subjects underwent an oral glucose tolerance test (OGTT). From the OGTT results, the participants were grouped as follows: young age and normal glucose tolerance (NGT), adult age and NGT, older age and NGT, IFG young subjects, IFG adult subjects, IFG older subjects, IGT young (Y-IGT) subjects, IGT adult (A-IGT) subjects, and IGT older (O-IGT) subjects. MAIN OUTCOME MEASURES: Insulin sensitivity and secretion, insulin clearance, and ß-cell function. RESULTS: Peripheral insulin sensitivity assessed using the Matsuda index, basal and glucose-stimulated insulin secretion, and ß-cell function estimated using the disposition index were decreased in IFG adult subjects and IFG older subjects compared with IFG young subjects. A-IGT and Y-IGT subjects exhibited a progressively greater degree of hepatic insulin resistance assessed using the liver insulin resistance index, and reduced insulin clearance compared with O-IGT subjects. In contrast, the Matsuda index did not differ among Y-IGT, A-IGT, and O-IGT subjects. Basal and glucose-stimulated insulin secretion and ß-cell function were lower in A-IGT and O-IGT subjects compared with Y-IGT individuals. CONCLUSIONS: Subjects with IFG or IGT exhibited different age-related pathophysiologic characteristics. A more precise phenotyping of subjects with IGT or IFG could help to better design individualized preventive approaches to counteract diabetes progression.

Higher serum levels of uric acid are associated with a reduced insulin clearance in non-diabetic individuals.

AIMS: Decreased insulin clearance has been reported to be associated with insulin resistance-related disorders and incident type 2 diabetes. The aim of this study was to evaluate whether higher levels of uric acid (UA), a known risk factor of type 2 diabetes, are associated with a reduced insulin clearance. METHODS: 440 non-diabetic individuals were stratified in tertiles according to serum UA levels. Insulin clearance and skeletal muscle insulin sensitivity were assessed by euglycemic hyperinsulinemic clamp. Hepatic insulin resistance was estimated by the liver IR index. RESULTS: Subjects with higher levels of UA displayed an unfavorable metabolic phenotype with a worse lipid profile, increased levels of 2-h post-load glucose levels, fasting, and 2-h post-load insulin levels, hsCRP, liver IR index, and lower levels of eGFR and skeletal muscle insulin sensitivity, in comparison to individuals with lower UA levels. Moreover, subjects with higher UA concentrations exhibited decreased levels of insulin clearance even after adjustment for age, gender, BMI, eGFR, and skeletal muscle insulin sensitivity. In a multivariate regression analysis model including several confounding factors, UA concentration was an independent predictor of insulin clearance (ß = - 0.145; P = 0.03). However, when liver IR index was included in the model, the independent association between UA levels and insulin clearance was not retained. Accordingly, in a mediation analysis, liver IR index was a mediator of the negative effects of UA levels on insulin clearance (t = - 2.55, P = 0.01). CONCLUSIONS: Higher serum levels of UA may affect insulin clearance by impairing hepatic insulin sensitivity.

Association between hemoglobin glycation index with insulin resistance and carotid atherosclerosis in non-diabetic individuals.

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 (ß = 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.

One-Hour Postload Hyperglycemia Confers Higher Risk of Hepatic Steatosis to HbA1c-Defined Prediabetic Subjects.

CONTEXT: Individuals with glycated hemoglobin (HbA1c)-defined prediabetes (HbA1c value of 5.7-6.4%) and 1-hour plasma glucose ≥155 mg/dL during an oral glucose tolerance test have an increased risk of developing type 2 diabetes. OBJECTIVE: To evaluate the degree to which HbA1c-defined prediabetes and 1-hour postload glucose ≥155 mg/dL individually and jointly associate with hepatic steatosis and related biomarkers. DESIGN AND PATIENTS: A cross-sectional analysis was performed on 1108 White individuals. SETTING: Ambulatory care. MAIN OUTCOME MEASURES: Anthropometric and metabolic characteristics including hepatic steatosis assessed by ultrasonography. RESULTS: Compared with the normal group (HbA1c <5.7%), HbA1c-defined prediabetic and diabetic individuals exhibit higher values of fasting, 1-hour, and 2-hour postload glucose; fasting and 2-hour postload insulin; triglycerides; uric acid; homeostasis model of assessment for insulin resistance; liver insulin resistance index; liver enzymes; and inflammatory biomarkers; and lower levels of high-density lipoprotein cholesterol and IGF-1. Prediabetic and diabetic subjects have increased risk of hepatic steatosis (1.5- and 2.46-fold, respectively). Stratifying participants according to HbA1c and 1-hour postload glucose, we found that individuals with HbA1c-defined prediabetes and 1-hour postload glucose ≥155 mg/dL have significantly higher risk of hepatic steatosis as compared with individuals with HbA1c-defined prediabetes but 1-hour postload glucose <155 mg/dL. Individuals with HbA1c-defined prediabetes and 1-hour postload glucose ≥155 mg/dL exhibit higher values of liver enzymes; fasting, 1-hour, and 2-hour postload glucose; insulin; triglycerides; uric acid; and inflammatory biomarkers; and lower levels of high-density lipoprotein and IGF-1. CONCLUSIONS: These data suggest that a value of 1-hour postload glucose ≥155 mg/dL may be helpful to identify a subset of individuals within HbA1c-defined glycemic categories at higher risk of hepatic steatosis.

One-hour post-load hyperglycemia combined with HbA1c identifies pre-diabetic individuals with a higher cardio-metabolic risk burden.

BACKGROUND AND AIMS: Evidence suggests that combining 1-hour plasma glucose ≥155 mg/dl during an oral glucose tolerance test (OGTT) with glycosylated hemoglobin (HbA1c) significantly increases their predictive power for incident diabetes, while their individual and joint associations with cardio-metabolic risk factors remain undefined. Herein, we evaluated whether 1-hour post-load plasma glucose ≥155 mg/dl combined with HbA1c may identify pre-diabetic individuals with a higher cardio-metabolic risk. METHODS: Anthropometric and metabolic characteristics, insulin sensitivity and insulin secretion assessed by OGTT-derived indexes, carotid intima-media thickness (IMT), pulse pressure, and rate pressure product were evaluated in 1495 individuals. RESULTS: As compared with subjects with 1-hour post-load glucose <155 mg/dl, individuals with 1-hour post-load glucose ≥155 mg/dl exhibited a significantly worse cardio metabolic profile, both in the group with HbA1c <5.7%, and in the group with prediabetes (HbA1c 5.7-6.4%). Specifically, in both groups, subjects with 1-hour post-load glucose ≥155 mg/dl had higher fasting and 2-h post-load glucose (p < 0.0001 for all in both groups), higher HOMA-IR (p < 0.0001 in both groups), and carotid IMT (p = 0.05 in the group with HbA1c <5.7% and p = 0.03 in the group HbA1c 5.7-6.4%), as well as lower Matsuda index, insulinogenic index and disposition index (p < 0.0001 in both groups), and lower insulin-stimulated glucose disposal (p < 0.0001 in the group with HbA1c <5.7% and p = 0.03 in the group HbA1c 5.7-6.4%). CONCLUSIONS: Hyperglycemia at 1-hour during an OGTT may be a useful tool to identify a subset of individuals within HbA1c-defined glycemic categories at higher risk of developing type 2 diabetes and cardiovascular disease.

Nonalcoholic fatty liver disease is associated with low circulating levels of insulin-like growth factor-I.

CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is associated with insulin resistance and cardiovascular disease. Among the potential factors that may account for the increased cardiometabolic risk, IGF-I is a plausible candidate because the liver is the main site of its production. OBJECTIVE: Our objective was to examine the relationship between NAFLD and IGF-I levels and to test the hypothesis that free fatty acids-induced insulin resistance might impair insulin-induced increase of GH receptor (GHR) expression in human hepatoma cells. SUBJECTS, DESIGN, AND SETTING: Five hundred three nondiabetic Caucasians participated in this ambulatory-care cross-sectional study. MAIN OUTCOME MEASURES: Cardiometabolic risk factors and liver ultrasound scanning were assessed. Insulin-induced expression of GHR in HuH7 human hepatoma cells exposed for 24 h to palmitate was determined by Western blotting and real-time PCR. RESULTS: After adjustment for age and gender, individuals with NAFLD had significantly higher body mass index, waist circumference, fasting insulin, triglycerides, homeostasis model assessment index, liver enzymes, and lower high-density lipoprotein cholesterol compared with control subjects. IGF-I levels were significantly lower in individuals with NAFLD (P = 0.001). Exposure of HuH7 hepatoma cells to palmitate caused a dose-dependent reduction in the insulin-induced increase of GHR expression. CONCLUSIONS: These data show that IGF-I levels are reduced in subjects with NAFLD and suggest that hepatic insulin resistance may affect IGF-I levels by modulating GH-stimulated synthesis of hepatic IGF-I.