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MicroRNA-122 (miR-122) is abundant in the liver and involved in lipid homeostasis, but its relevance to the long-term risk of developing metabolic disorders is unknown. We therefore measured circulating miR-122 in the prospective population-based Bruneck Study (n = 810; survey year 1995). Circulating miR-122 was associated with prevalent insulin resistance, obesity, metabolic syndrome, type 2 diabetes, and an adverse lipid profile. Among 92 plasma proteins and 135 lipid subspecies quantified with mass spectrometry, it correlated inversely with zinc-α-2-glycoprotein and positively with afamin, complement factor H, VLDL-associated apolipoproteins, and lipid subspecies containing monounsaturated and saturated fatty acids. Proteomics analysis of livers from antagomiR-122-treated mice revealed novel regulators of hepatic lipid metabolism that are responsive to miR-122 inhibition. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT, n = 155), 12-month atorvastatin reduced circulating miR-122. A similar response to atorvastatin was observed in mice and cultured murine hepatocytes. Over up to 15 years of follow-up in the Bruneck Study, multivariable adjusted risk ratios per one-SD higher log miR-122 were 1.60 (95% CI 1.30-1.96; P < 0.001) for metabolic syndrome and 1.37 (1.03-1.82; P = 0.021) for type 2 diabetes. In conclusion, circulating miR-122 is strongly associated with the risk of developing metabolic syndrome and type 2 diabetes in the general population. [ABSTRACT FROM AUTHOR]

We adapted a minimal model to assess beta-cell function during a hyperglycemic glucose clamp and to uncover peculiar aspects of the relationship among beta-cell function, plasma glucose, and insulin sensitivity (IS) in offspring of Caucasian patients with type 2 diabetes (OfT2D). We pooled two data sets of OfT2D (n = 69) and control subjects (n = 45) with normal glucose regulation. Plasma C-peptide was measured during a hyperglycemic clamp ( approximately 10 mmol/l) to quantify model-based first-phase secretion and glucose sensitivity of second-phase secretion (beta). IS was quantified during the hyperglycemic clamp. In the pooled data, first-phase secretion was linearly and negatively related to fasting plasma glucose, but not IS; OfT2D lay on a distinct line shifted to the left of the control subjects. In contrast, beta was negatively related to IS, and OfT2D lay on a distinct line shifted more and more to the left of the control subjects, as IS was worse. Thus, in OfT2D lower beta-cell adaptive responses exist between ambient glycemia and first-phase insulin secretion and between IS and second-phase secretion. Under conditions leading to decreased insulin sensitivity, these disturbed relationships may lead to progression to diabetes in OfT2D. [ABSTRACT FROM AUTHOR]

The rising tide of diabetes (DM) calls for strategies applicable at large scale to anticipate diagnosis at the earliest disease stages. However, no conclusive evidence exists on the most effective DM screening program. We tested whether random capillary blood glucose (RCBG), a validated DM risk questionnaire (FINDRISC), or both, may be applied as universal screening strategy in a 4-year (2015-18) multi-center study involving all individuals presenting to the information desks during the World Diabetes Day and similar initiatives in two metropolitan areas of Northern Italy. In case of high FINDRISC scores (>14 points) and/or RCGB levels suggestive for DM (≥200 mg/dL within 2h after last meal/sugar drink;≥150 mg/dL within 2-5h; ≥125 mg/dL, >5h), people were invited to the Diabetes Center (DC) for laboratory confirmation by fasting plasma glucose and A1c. The FINDRISC was also advertised on newspapers and flyers in squares, hospitals and pharmacies of both cities. Overall, 62,827 flyers were distributed and ∼400.000 inhabitants were exposed to the advertisements. Eventually, 154 individuals reporting high FINDRISC scores presented for a laboratory check and diagnosis was confirmed in 18 (11.7%). Among 8,563 individuals undergoing RCBG, 341 (4%) had glucose levels suggestive for DM; 86 had a laboratory check and DM was confirmed in 36 (41.9%). In addition to RCBG, 3,351 subjects also completed the FINDRISC and 480 (14.3%) reported high scores. Of them, 397 (82.7%) presented to the DC and 40 (10.1%) had diagnosis confirmed. In 30 individuals, both FINDRISC and RCBG were suggestive for DM and diagnosis was confirmed in 17/27 subjects eventually presented to the DC (63.0%). These data suggest that RCBG outperforms FINDRISC to identify unknown DM. The simultaneous presence of FINDRISC and RCBG suggestive for DM appears even more effective. Poor adherence to laboratory check in high-risk cases calls for initiatives to raise public awareness on the deleterious concequences of untreated DM. Disclosure: M. Dauriz: None. E. Bonora: Advisory Panel; Self; Lilly Diabetes, Novartis AG, Sanofi. Speaker's Bureau; Self; Abbott, Lilly Diabetes, Novo Nordisk A/S, Sanofi. Funding: Italian Ministry of Health (RF-2011-02350193) [ABSTRACT FROM AUTHOR]

The Metabolic Syndrome is a risk factor for type: 2 diabetes (T2DM). However, previous studies demonstrated that any component of the Metabolic Syndrome can predict T2DM. Among subjects without the Metabolic Syndrome many have one or two components of the syndrome, and this may lead to an underestimate of the true diabetes risk in subjects with the: Metabolic Syndrome. In the present study we assessed the 10-yr risk of T2DM in subjects aged 40-79 years from the general population living in Bruneck, north-eastern Italy. The Metabolic Syndrome was diagnosed by NCEP-ATP III criteria. Incident cases of T2DM were 76 out of 857. In the 169 subjects with the Metabolic Syndrome at baseline the sex- and age-adjusted odds ratio (OR) for T2DM was 4.4 (95% CI 2.7-7.2). As compared to subjects without any metabolic components of the Metabolic Syndrome the ORs in those with 1, 2, 3, 4/5 components were 6.4 (0.8-49.6, p=0.08), 18.5 (2.5-139, p=0.005), 22.2 (2.9-172, p=0.003) and 119 (15.1-942, p<0.001), respectively (overall p<0.001). Among components of the Metabolic Syndrome, IFG was the stronger risk factor (OR 12.2, 7.1-20.5, p<0.001), but also high waist circumference (5.4, 3.0-9.5, p<0.001), hypertension (4.4, 2.1-9.0, p<0.001), high triglycerides (1.7, 1.1 -2.8, p=0.03) and low HDL-cholesterol (1.8, 1.0-3.1, p=0.05) were predictors of T2DM. The risk of T2DM was very high in subjects with the Metabolic Syndrome also when insulin sensitivity was normal (quartiles 1-3 of HOMAIR)(ORs 12.3, 1.4-109, p=0.024 in those with 3, and 38.0, 3.1-471,13=0.005 in those with 4/5 abnormalities vs. those with no abnormality). In conclusion, the risk of T2DM in subjects with the Metabolic Syndrome is very high when the reference category is composed by subjects without any metabolic abnormality. The risk is high also when insulin resistance was estimated to be normal. [ABSTRACT FROM AUTHOR]

The clinical utility of diagnosing the Metabolic Syndrome has been recently challenged. One of the critiques has been that the cardiovascular risk in subjects affected is not substantially different from the risk observed in diabetes mellitus or hypertension, which are frequent components of this syndrome. In the present study we assessed the risk of coronary heart disease (CHD) in subjects with the Metabolic Syndrome extracted from the general population living in Bruneck, north-eastern Italy. A random sample of 840 subjects, aged 40-79 years, free of CHD at baseline was followed-up for 15 years. CHD was a composite endpoint including fatal and non-fatal myocardial infarction and confirmed angina pectoris. The Metabolic Syndrome was diagnosed at baseline by AHA-NHBLI, IDF or WHO criteria. Subjects with the syndrome were compared to subjects without the syndrome as well as to subjects without any metabolic abnormality at baseline, after adjusting for sex, age, smoking and LDL-cholesterol. Incident CHD cases during follow-up were 89. Subjects developing CHD had a poorer metabolic profile at baseline. The Metabolic Syndrome was very prevalent with all diagnostic criteria, ranging from 24.4% (WHO criteria) to 32.6% (IDF criteria). Also subjects with one or two metabolic disorders were very frequent (59% of cases). The risk of CHD in subjects with the Metabolic Syndrome was 1.4 to 2.3 higher when subjects without the syndrome were the reference category. The risk, however, was several-fold higher when subjects without any metabolic abnormality composed the reference category: in Cox proportional model the hazard ratio Was 12.5 (95% CI, 1.7-92.7, p=0.014) when AHA-NHLBI criteria were used. The corresponding figures with IDF and WHO criteria were 13.6 (1.8-100, p=0.01) and 5.9 (2.0-17.6,p<0.001), respectively. Subjects with the Metabolic Syndrome by AHA-NHLBI criteria had a 13.5% probability of developing CHD over 15 years vs. 0.9% in subjects free of any metabolic abnormality at baseline. These results clearly indicate that, when compared to the most appropriate reference category, subjects with the Metabolic Syndrome have a very high cardiovascular risk. Physicians should identify and treat carefully subjects with the Metabolic Syndrome. [ABSTRACT FROM AUTHOR]