Metabolomic discovery of biomarkers of type 2 diabetes (T2D) risk may reveal etiological pathways and help to identify individuals at risk for disease. We prospectively investigated the association between serum metabolites measured by targeted metabolomics and risk of T2D in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam (27,548 adults) among all incident cases of T2D (n = 800, mean follow-up 7 years) and a randomly drawn subcohort (n = 2,282). Flow injection analysis tandem mass spectrometry was used to quantify 163 metabolites, including acylcarnitines, amino acids, hexose, and phospholipids, in baseline serum samples. Serum hexose; phenylalanine; and diacyl-phosphatidylcholines C32:1, C36:1, C38:3, and C40:5 were independently associated with increased risk of T2D and serum glycine; sphingomyelin C16:1; acyl-alkyl-phosphatidylcholines C34:3, C40:6, C42:5, C44:4, and C44:5; and lysophosphatidylcholine C18:2 with decreased risk. Variance of the metabolites was largely explained by two metabolite factors with opposing risk associations (factor 1 relative risk in extreme quintiles 0.31 [95% CI 0.21–0.44], factor 2 3.82 [2.64–5.52]). The metabolites significantly improved T2D prediction compared with established risk factors. They were further linked to insulin sensitivity and secretion in the Tübingen Family study and were partly replicated in the independent KORA (Cooperative Health Research in the Region of Augsburg) cohort. The data indicate that metabolic alterations, including sugar metabolites, amino acids, and choline-containing phospholipids, are associated early on with a higher risk of T2D.

Cancer control by adaptive immunity involves a number of defined death and clearance mechanisms. However, efficient inhibition of exponential cancer growth by T cells and interferon-γ (IFN-γ) requires additional undefined mechanisms that arrest cancer cell proliferation. Here we show that the combined action of the T-helper-1-cell cytokines IFN-γ and tumour necrosis factor (TNF) directly induces permanent growth arrest in cancers. To safely separate senescence induced by tumour immunity from oncogene-induced senescence, we used a mouse model in which the Simian virus 40 large T antigen (Tag) expressed under the control of the rat insulin promoter creates tumours by attenuating p53- and Rb-mediated cell cycle control. When combined, IFN-γ and TNF drive Tag-expressing cancers into senescence by inducing permanent growth arrest in G1/G0, activation of p16INK4a (also known as CDKN2A), and downstream Rb hypophosphorylation at serine 795. This cytokine-induced senescence strictly requires STAT1 and TNFR1 (also known as TNFRSF1A) signalling in addition to p16INK4a. In vivo, Tag-specific T-helper 1 cells permanently arrest Tag-expressing cancers by inducing IFN-γ- and TNFR1-dependent senescence. Conversely, Tnfr1(-/-)Tag-expressing cancers resist cytokine-induced senescence and grow aggressively, even in TNFR1-expressing hosts. Finally, as IFN-γ and TNF induce senescence in numerous murine and human cancers, this may be a general mechanism for arresting cancer progression.

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OBJECTIVE -The ␣ 2 -Heremans-Schmid glycoprotein (AHSG; fetuin-A in animals) impairs insulin signaling in vitro and in rodents. Whether AHSG is associated with insulin resistance in humans is under investigation. In an animal model of diet-induced obesity that is commonly associated with hepatic steatosis, an increase in Ahsg mRNA expression was observed in the liver. Therefore, we hypothesized that the AHSG plasma protein, which is exclusively secreted by the liver in humans, may not only be associated with insulin resistance but also with fat accumulation in the liver.RESEARCH DESIGN AND METHODS -Data from 106 healthy Caucasians without type 2 diabetes were included in cross-sectional analyses. A subgroup of 47 individuals had data from a longitudinal study. Insulin sensitivity was measured by a euglycemic-hyperinsulinemic clamp, and liver fat was determined by 1 H magnetic resonance spectroscopy.RESULTS -AHSG plasma levels, adjusted for age, sex, and percentage of body fat, were higher in subjects with impaired glucose tolerance compared with subjects with normal glucose tolerance (P ϭ 0.006). AHSG plasma levels were negatively associated with insulin sensitivity (r ϭ Ϫ0.22, P ϭ 0.03) in cross-sectional analyses. Moreover, they were positively associated with liver fat (r ϭ 0.27, P ϭ 0.01). In longitudinal analyses, under weight loss, a decrease in liver fat was accompanied by a decrease in AHSG plasma concentrations. Furthermore, high AHSG levels at baseline predicted less increase in insulin sensitivity (P ϭ 0.02).CONCLUSIONS -We found that high AHSG plasma levels are associated with insulin resistance in humans. Moreover, AHSG plasma levels are elevated in subjects with fat accumulation in the liver. This is consistent with a potential role of AHSG as a link between fatty liver and insulin resistance. Diabetes Care 29:853-857, 2006I nsulin resistance plays a crucial role in the development of type 2 diabetes (1). Multiple mechanisms are thought to be involved in its pathogenesis. Among them, the human ␣ 2 -Heremans-Schmid glycoprotein (AHSG) was found to be important in animals and in in vitro studies. It is an abundant serum protein in mammals. Bovine and murine fetuin-A and pp63 in rats are homologues of AHSG (2,3). In humans, except for the tongue and the placenta, it is exclusively expressed in the liver (4). It is a natural inhibitor of the insulin-stimulated insulin receptor tyrosine kinase (3). Acute injection of human recombinant AHSG inhibi t e d i n s u l i n -s t i m u l a t e d t y r o s i n e phosphorylation of the insulin receptor and insulin receptor substrate-1 in rat liver and skeletal muscle (3). In addition, AHSG knockout mice display improved insulin sensitivity and are resistant to weight gain on a high-fat diet (5).While these data reflect that AHSG is an important candidate among the factors that induce insulin resistance, the role of this protein in the natural history of type 2 diabetes is still unclear (6). Recent reports from genetic studies suggest that single nucleotide polymor...

Type 2 diabetes and cardiovascular disease represent a serious threat to the health of the population worldwide. Although overall adiposity and particularly visceral adiposity are established risk factors for these diseases, in the recent years fatty liver emerged as an additional and independent factor. However, the pathophysiology of fat accumulation in the liver and the cross-talk of fatty liver with other tissues involved in metabolism in humans are not fully understood. Here we discuss the mechanisms involved in the pathogenesis of hepatic fat accumulation, particularly the roles of body fat distribution, nutrition, exercise, genetics, and gene-environment interaction. Furthermore, the effects of fatty liver on glucose and lipid metabolism, specifically via induction of subclinical inflammation and secretion of humoral factors, are highlighted. Finally, new aspects regarding the dissociation of fatty liver and insulin resistance are addressed.

Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders.

A BMI in the normal range associates with a decreased risk of cardiometabolic disease and all-cause mortality. However, not all subjects in this BMI range have this low risk. Compared to people who are of normal weight and metabolically healthy, subjects who are of normal weight but metabolically unhealthy (∼20% of the normal weight adult population) have a greater than 3-fold higher risk of all-cause mortality and/or cardiovascular events. Here we address to what extent major risk phenotypes determine metabolic health in lean compared to overweight and obese people and provide support for the existence of a lipodystrophy-like phenotype in the general population. Furthermore, we highlight the molecular mechanisms that induce this phenotype. Finally, we propose strategies as to how this knowledge could be implemented in the prevention and treatment of cardiometabolic diseases in different stages of adiposity in routine clinical practice.