ORONARY HEART DISEASE (CHD) is a major cause of disability and premature death throughout the world. 1 Epidemiological studies have demonstrated an inverse association between physical fitness and the incidence of CHD or allcause mortality in healthy or asymptomatic participants. Physical fitness is typically expressed as cardiorespiratory fitness (CRF) and is assessed by exercise tolerance testing 2 ; however, it is rare for clinicians to consider CRF when evaluating future risk of CHD. 3 A major reason for lack of consideration of CRF as a marker of CHD risk may be that the quantitative association of CRF for cardiovascular risk is not well established. The degree of risk reduc-CME available online at www.jamaarchivescme.com and questions on p 2053.
Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C epsilon activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.
OBJECTIVETo systematically evaluate the association between serum uric acid (SUA) level and subsequent development of type 2 diabetes.RESEARCH DESIGN AND METHODSWe searched Medline (31 March from 1966 to 2009) and Embase (31 March from 1980 to 2009) for observational cohort studies examining the association between SUA and the risk of type 2 diabetes by manual literature search. Relative risks (RRs) for each 1 mg/dl increase in SUA were pooled by using a random-effects model. The studies included were stratified into subgroups representing different study characteristics, and meta-regression analyses were performed to investigate the effect of these characteristics on the association between SUA level and type 2 diabetes risk.RESULTSThe search yielded 11 cohort studies (42,834 participants) that reported 3,305 incident cases of type 2 diabetes during follow-up periods ranging from 2.0 to 13.5 years. The pooled RR of a 1 mg/dl increase in SUA was 1.17 (95% CI 1.09–1.25). Study results were consistently significant (i.e., >1) across characteristics of participants and study design. Publication bias was both visually and statistically suggested (P = 0.03 for Egger's test, 0.06). Adjustment for publication bias attenuated the pooled RR per mg/dl increase in SUA (RR 1.11 [95% CI 1.03–1.20]), but the association remained statistically significant (P = 0.009).CONCLUSIONSThe current meta-analysis suggests that SUA level is positively associated with the development of type 2 diabetes regardless of various study characteristics. Further research should attempt to determine whether it is effective to utilize SUA level as a predictor of type 2 diabetes for its primary prevention.
A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca 2؉ in response to glucose, and thereby glucoseinduced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5؊͞؊ islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5؊͞؊ islets. Furthermore, exposure of LRP5؉͞؉ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that Wnt͞LRP5 signaling contributes to the glucose-induced insulin secretion in the islets.and LRP6 are coreceptors involved in the Wnt signaling pathway (1-6). The Wnt signaling pathway plays a pivotal role in embryonic development (7,8) and oncogenesis (9) through various signaling molecules including Frizzled receptors (10), recently characterized LRP5 and LRP6 (1-6), and Dickkopf proteins (4, 6). In addition, the Wnt signaling is also involved in adipogenesis by negatively regulating adipogenic transcription factors (Tcfs) (11). Although Wnt signaling has been characterized in both developmental and oncogenic processes, little is known about its function in the normal adult.Recent studies have revealed that loss of function mutations in the LRP5 gene cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (12). LRP5 is expressed in osteoblasts and transduces Wnt signaling via the canonical pathway, thereby modulating bone accrual development (12, 13). A point mutation in a ''propeller'' motif in LRP5 causes a dominant-positive high bone density by impairing the action of a normal antagonist of the Wnt pathway, Dickkopf, thereby increasing Wnt signaling (14,15). In addition, the human LRP5 gene is mapped within the region (IDDM4) linked to type 1 diabetes on chromosome 11q13 (16).In previous studies, we and others showed that LRP5 is highly expressed in many tissues, including hepatocytes and pancreatic beta cells (17,18). We also showed that LRP5 can bind apolipoprotein E (apoE) (18). This finding raises the possibility that LRP5 plays a role in the hepatic clearance of apoE-containing chylomicron remnants, a major plasma lipoprotein carrying diet-derived cholesterol.To evaluate the in vivo roles of LRP5, we generated LRP...
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