KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.This work was supported by the Wellcome Trust (098497/Z/12/Z; 077016/Z/05/Z; 096106/Z/11/Z) (ISF and LRP), Medical Research Council (MC_U106179471) (NW), NIHR Cambridge Biomedical Research Centre (ISF, IB and SOR), and European Research Council (ISF). This study makes use of data generated by the UK10K Consortium (WT091310). A full list of the investigators who contributed to the generation of the data is available from http://www.UK10K.org.This is the final published version. It first appeared at http://www.cell.com/abstract/S0092-8674%2813%2901276-2

Micronutrients and Diabetic Retinopathy A Systematic Review

Background: We have evaluated the evidence for the association between intake and blood levels of micronutrients and diabetic retinopathy. Treatment for diabetic retinopathy requires significant clinical input and specialist ophthalmologic care. Micronutrients, including vitamin C, vitamin E, and magnesium, may interfere with pathologic mechanisms of diabetic retinopathy and potentially alter its risk. Methods: We conducted a search of epidemiologic literature in PubMed and Embase from 1988 to May 2008, using keywords for exposures, including magnesium, ascorbic acid, alpha-tocopherol and antioxidants, and outcomes, including diabetic retinopathy. Two authors independently extracted data and assessed the quality of the studies using the Newcastle-Ottawa Scale. The overall quality of evidence was graded as I ( highest), II, or III ( lowest). Results: Of the 766 studies identified, we reviewed 15 studies, comprising 4094 individuals. For vitamin C, hospital-based studies reported an inverse association between plasma levels with retinopathy, whereas population-based studies showed no association between dietary intake and retinopathy. For vitamin E, there was no association with dietary intake or plasma levels and retinopathy. For magnesium, a single prospective analysis showed an association between low levels in plasma and progression of retinopathy, but cross-sectional studies reported inconsistent results. In the assessment of quality, population-based studies had higher ratings than hospital-based studies. Conclusions: The evidence suggests that dietary intake or plasma levels of vitamins C and E and magnesium do not seem to be associated with diabetic retinopathy. Because of differences in study designs and measurement of micronutrients, incomplete ascertainment of retinopathy, and residual confounding, these findings require confirmation