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.

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.

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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.

Graphical abstract

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 18 F-fluorodeoxyglucose positron emission tomography combined with a euglycemichyperinsulinemic 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 5 10), 2) those with NGT 1-h high (n 5 10), 3) and those with IGT (n 5 10). RESULTS After adjusting for age, sex, and BMI, both subjects with NGT 1-h high (23.7 6 6.4 mmol/min/100 mg; P 5 0.024) and those with IGT (16.4 6 6.0 mmol/min/ 100 mg; P < 0.0001) exhibited a significant reduction in global myocardial MRGlu; this value was 32.8 6 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 5 0.441; P 5 0.019) and negatively correlated with 1-h (r 5 20.422; P 5 0.025) and 2-h (r 5 20.374; P 5 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.

Background: 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.Methods: Incident rate of type 2 diabetes and changes in insulin sensitivity and β-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 β-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 postload glucose, family history of type 2 diabetes and smoking habit, HDL concentration at baseline was an independent predictor of β-cell function decline over the followup (β = .30, P = .0001). Mediation analysis showed that the association between lower HDL levels at baseline and increased risk of incident diabetes was mediated by β-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 β-cell function decline over time.

Higher serum levels of UA may affect insulin clearance by impairing hepatic insulin sensitivity.