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Objective: Statin therapy has been linked to an increased risk of type 2 diabetes in high-risk populations; however, the pathophysiology of this association remains to be clarified. We investigated glucagon suppression and its relationship with insulin resistance in prediabetic subjects undergoing ator vastatin therapy; in addition, we studied molecular insulin signaling in pancreatic a-cells exposed to atorvastatin in vitro. Design and methods: Fifty subjects with prediabetes were divided into two groups b ased on atorvastatin therapy. All subjects underwent an oral glucose tolerance test. Early (0-30 min), late (30-120 min) and overall (0-120 min) glucagon suppression were evaluated. Insulin sensitivity was estimated by the insulin sensitivity index (ISI0-120). Insulin signaling pathway and insulin-mediated glucagon suppression were investigated in pancreatic aTC1-6 cells chronically exposed (24 or 48 h) to atorvastatin (100 ng/mL). Results: Individuals on statin therapy (n = 26) showed a significantly reduced early (0-30 min) (P = 0.003) and overall (0-120 min) (P = 0.01) glucagon suppression compared with controls (n = 24). In multivariate regression analysis, early glucagon suppression (0-30 min) exhibited a significant correlat ion with statin therapy. Regression analysis showed a significant association between ISI 0-120 and early0-30 (r = 0.33, P < 0.05) and overall0-120 (r = 0.38, P < 0.05) glucagon suppression. Moreover, in aTC1-6 cells atorvastatin treatment affected insulin-mediated glucagon suppression, insulin receptor phosphorylation and IRS-1-AKT pathway signaling. Conclusions: Prediabetic patients undergoing statin therapy exhibit impaire d glucagon suppression associated with lower insulin sensitivity. Our data revealed a new molecular as pect behind the deregulation of insulin sensitivity secondary to statin exposure. [ABSTRACT FROM AUTHOR]

OBJECTIVE We investigated the cardiovascular risk pro le in subjects with prediabetes and new-onset type 2 diabetes identified by glycated hemoglobin A1c (HbA1c) according to the new American Diabetes Association criteria. RESEARCH DESIGN AND METHODS Arterial stiffness, intima-media thickness (IMT), soluble receptor for advanced glycation end products (sRAGEs), and oral glucose tolerance test (OGTT) were evaluated in 274 subjects without a previous history of diabetes. The subjects were stratified into three groups according to the HbA1c levels. RESULTS The subjects with prediabetes (n = 117, HbA1c 5.7-6.4% [39-46 mmol/mol]) showed a higher augmentation (Aug), augmentation index (Augl), and IMT compared with those with lower HbA1c; however, these values were similar to those of subjects with HbA1c >6.5%(48mmol/mol). When we further analyzed the subjects with prediabetes but included only subjects with normal glucose tolerance (NT) in the analysis, Augl and IMT still remained significantly higher than their levels in control subjects with HbA1c <5.7% (39 mmol/mol). After multiple regression analyses including several cardiovascular risk factors, only HbA1c, age, and sRAGE were significantly correlated with the IMT, whereas age and 1-h postload glucose were the major determinants of Augl. CONCLUSIONS Our data show that subjects with prediabetes according to HbA1c, but with both NT according to the OGTT and normal fasting glycemia, have an altered IMT and Augl. These data suggest that a simple, reproducible, and less expensive marker such as HbA1c may be better able to identify prediabetic subjects at high cardiovascular risk compared with fasting glycemia or OGTT alone. [ABSTRACT FROM AUTHOR]

Objective: Obesity is widely acknowledged as a critical risk factor for metabolic complications. Among obese subjects, there is a phenotype of metabolically healthy but obese (MHO) individuals that shows a favorable cardiometabolic risk profile. We aimed to evaluate the potential mechanisms underlying the metabolic profile of this subset, including alpha and beta cell function and entero-insular axis. Design and Methods: One hundred twenty-nine obese and 24 nonobese subjects were studied. Obese participants were defined as MHO or at-risk obese, according to the homeostasis model of assessment-insulin resistance (HOMA-IR) index (MHO: lower tertile of HOMA-IR, n = 43; at-risk: upper tertile of HOMA-IR index, n = 41). Insulin, glucagon, and incretin responses after a 120′ oral glucose tolerance test (75-g OGTT) were investigated. Results: During OGTT, MHO individuals showed in comparison with at-risk subjects: lower fasting and afterloads plasma levels of glucose, insulin, and C-peptide; higher disposition index; lower fasting ( P = 0.004) and at 30′ ( P = 0.01) plasma glucose-dependent insulinotropic polypeptide (GIP) levels; lower area under the curve (AUC) (0-30) for GIP ( P = 0.008); higher glucagon-like peptide-1 (GLP-1) plasma levels at 90′ ( P = 0.02) and 120′ ( P = 0.02); lower glucagon plasma levels at baseline ( P = 0.04) and at 30′ ( P = 0.03); and appropriate glucagon suppression after the oral glucose load. Conclusions: MHO subjects show, as well as normal-weight individuals, a lower diabetogenic profile by virtue of higher disposition index and unaffected entero-insular axis. At-risk obese individuals present increased GIP levels that might play a role in determining increased glucagon secretion and inappropriate glucagon responses after glucose load, thus contributing to impaired glucose homeostasis. [ABSTRACT FROM AUTHOR]

Background and aims: Metabolic syndrome (MS) is a high-risk condition for type 2 diabetes, a disease characterized by insulin resistance and insulin secretion abnormalities. Insulin resistance has been widely characterized in MS subjects while insulin secretion has been poorly investigated. The present study was hence undertaken to further investigate the &agr; and &bgr; cell function and entero-insular axis in this pre-diabetic condition. Materials and methods: Using 120' oral glucose tolerance test (OGTT, 75 g) and 60' intravenous glucose tolerance test (IVGTT, 0.3 g/kg), we studied &agr; and &bgr; cell function, insulin resistance, and incretin levels in 96 subjects with normal fasting glucose and normal glucose tolerance to OGTT, with (MS+, n=29) and without MS (MS-, n=67). Results: MS+ individuals showed in comparison with MSK: higher insulinogenic index (IG30) and higher area under the curve (AUC) (0-120) for glucose and insulin during the OGTT, P<0.05; higher AUC (0-10) for glucose (P<0.05) but similar first phase insulin secretion (P=NS) as measured by δAIRG and AUC (0-10) for insulin during the IVGTT; increased AUC (0-60) for insulin during the IVGTT (P=0.04); higher GIP levels at 300 (P=0.03), 600 (P=0.01), 900 (P=0.003), and 1200 (P=0.004); higher AUC (0-120) for GIP (P=0.007); similar AUC (0-120) for GLP-1 during the OGTT; and delayed glucagon suppression after the OGTT. Conclusion: NGT subjects with MS showed increased GIP secretion that could be responsible for the delayed glucagon suppression during the OGTT, thereby suggesting a role for incretins in regulating glucose homeostasis in this condition. [ABSTRACT FROM AUTHOR]

We investigated the correlation of the soluble receptor for advanced glycation end products (sRAGE) and endogenous secretory RAGE (esRAGE) with markers of cardiovascular disease in subjects with normal glucose tolerance (NGT) and 1 h postload glucose ≥155 mg/dL after an oral glucose tolerance test. We stratified 282 subjects without a previous diagnosis of diabetes into three groups: 123 controls (NGT and 1 h postload glycemia <155 mg/dL), 84 NGT and 1 h postload glycemia ≥155 mg/dL (NGT 1 h high), and 75 subjects with impaired fasting glucose and/or impaired glucose tolerance (IFG/IGT). NGT 1 h high subjects exhibited lower esRAGE (0.36 ± 0.18 vs. 0.4 5 ± 0.2, p < 0.05) and higher S100A12 levels than controls (5684 (3193.2–8295.6) vs. 3960.1 (2101.8–7419), p < 0.05). Furthermore, they showed an increased pulse wave velocity (PWV) and intima–media thickness (IMT). No differences were found between the NGT 1 h high group and the IFG/IGT group regarding cardiometabolic profiles. After multiple regression analyses, esRAGE was associated with glycated hemoglobin (HbA1c) and high-sensitivity C-reactive protein (hs-CRP). Age, HbA1c, and esRAGE were the determinants of IMT, whereas S100A12 and systolic pressure were the determinants of PWV. The NGT 1 h high group exhibited low esRAGE levels and an altered cardiometabolic profile. HbA1c, S100A12, and hs-CRP were associated with these alterations. In conclusion, subjects with NGT are not a homogeneous population, and they present different cardiovascular and glycometabolic risks. [ABSTRACT FROM AUTHOR]

Background and aims We investigated serum -hydroxyvitamin D levels [25(OH)D] and their correlation with early markers of cardiovascular disease in subjects with pre-diabetes. We particularly focused on individuals identified only by glycated hemoglobin A 1c (HbA 1c 5.7–6.4%) according to the American Diabetes Association criteria but who were normotolerant (NT) after oral glucose tolerance test (OGTT) and had normal fasting glucose (NFG). Methods 25(OH)D levels, HbA 1c , OGTT, arterial stiffness and intima-media thickness (IMT) were evaluated in 286 subjects without history of diabetes. Subjects were stratified into four groups: controls with HbA 1c <5.7%, NFG and NT; prediabetic patients with pre-diabetes according to only HbA 1c (HbA 1c 5.7–6.4% and NFG/NT); subjects with impaired fasting glucose and impaired glucose tolerance (IFG/IGT); new onset type 2 diabetes (HbA 1c ≥ 6.5%). Results Subjects with NFG/NT and HbA 1c 5.7–6.4% (n = 83) showed lower 25(OH)D levels compared with controls (n = 80) (21.7 [15.8–31.1] vs 23.1 [17.1–29.7] ng/mL, P = 0.009); these values were similar to those of the IFG/IGT group and were higher but not significantly different from subjects with new onset type 2 diabetes. After multiple regression analyses, only HbA 1c and BMI were independently associated with 25(OH)D levels. Age, HbA 1c and 25(OH)D were the major determinants of Augmentation Index. No independent association between 25(OH)D and IMT was found. Conclusions Subjects with pre-diabetes (HbA 1c 5.7–6.4% and NFG/NT) had significantly reduced 25(OH)D levels compared with controls. Reduction of 25(OH)D levels is inversely associated with arterial stiffness independently of classical risk factors and inflammatory markers. Based on these data, subjects with NFG and NT are not a homogeneous population of patients, and they present different cardiovascular and glycometabolic risks. Our data suggest considering HbA 1c as a reliable marker of cardiovascular and metabolic risk independent of fasting and post-load glycemia. [ABSTRACT FROM AUTHOR]