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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/advagg_css\/css__ce2QY63WIanKyr8eSq7eavr1XQRRmFD6ZSmwpyJi8lM__zXwFqpqmxrZOXXcd_TpBQpjuELbmIP9wBR5UuTDWAO4__YJWWMMdfCJuAFm5cUEp88OsodhO3ZA-2lzRfoBsSlk4.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EGenetic variants identified during the study of diabetes can be used as a tool to understand the cellular and molecular mechanisms that underlie the pathogenesis of diabetes. These variants can then be used to identify biomarkers, develop new therapies, and stratify patients to the most effective treatments, which is discussed in this article.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPrevention \u0026amp; Screening\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes Mellitus\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EEndocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EPrevention \u0026amp; Screening\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EFor the past 20 years, Anna L. Gloyn, DPhil, Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom, has been studying genetic variants identified during the study of diabetes as a tool to understand the cellular and molecular mechanisms that underlie the pathogenesis of diabetes. Her goal is to identify biomarkers, develop new therapies, and stratify patients to the most effective treatments.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EEvidence that this approach can be successful comes from a 2004 study that identified heterozygous activating mutations in the gene-encoding Kir6.2 subunit of the adenosine triphosphate (ATP)-sensitive potassium channel in pancreatic \u03b2 cells as the cause of permanent neonatal diabetes [Gloyn AL et al. \u003Cem\u003EN Engl J Med.\u003C\/em\u003E 2004]. Consequently, the \u03b2 cells of these patients were unable to secrete insulin in response to glucose. This knowledge led to successful treatment of these patients with sulfonylureas, which target the K\u003Csub\u003EATP\u003C\/sub\u003E channel and restore insulin secretion.\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EGenome-wide association studies have been very successful in identifying regions of the genome robustly associated with type 2 diabetes mellitus (T2DM) risk. However, most of these signals map to regions of the genome that do not code for proteins, leaving uncertainty regarding the transcript and the proteins through which they exert their effect on diabetes. The current challenge, Prof Gloyn noted, is to move from the approximately 80 associated regions of the genome and identify the target proteins that will unlock the biology of diabetes.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EProf Gloyn then discussed the role coding variants, which are independently associated with diabetes risk or glycemic traits and independent from these genome-wide association study signals, could play in identifying these proteins. She discussed published data regarding a region of the genome associated with fasting plasma glucose (FPG) levels in people without diabetes. Two strong biological candidate genes close to the noncoding variant were identified as being possibly responsible [Bouatia-Naji N et al. \u003Cem\u003EScience\u003C\/em\u003E. 2008; Chen WM et al. \u003Cem\u003EJ Clin Invest\u003C\/em\u003E. 2008]. The first candidate gene was \u003Cem\u003EG6PC2\u003C\/em\u003E, which encodes for the islet-specific glucose-6-phosphatase catalytic subunit, known to catalyze the reverse reaction mediated by the pancreatic \u03b2-cell sensor glucokinase. The second was \u003Cem\u003EABCB11\u003C\/em\u003E, which encodes for an ATP-binding cassette transporter and for part of the bile salt export pump. \u003Cem\u003EABCB11\u003C\/em\u003E was also considered a strong candidate because changes in bile salt secretion and bile acid pools can influence lipid and glucose metabolism.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EThe International GoT2D and T2D-GENES consortia performed exome sequencing in about 6500 patients with T2DM and a similar number of controls drawn from 5 different ancestries to obtain a more complete picture of the coding variation and to potentially resolve the uncertainty as to which of the 2 genes is responsible for the differences in FPG. This exome sequencing was supported by genotyping from more than 80 000 individuals of European ancestry, including 33 000 nondiabetic individuals for whom FPG levels were available. Two coding variants identified in \u003Cem\u003EG6PC2\u003C\/em\u003E were significantly associated with FPG levels, but no coding variants were identified for \u003Cem\u003EABCB11\u003C\/em\u003E. Coding variants in \u003Cem\u003EG6PC2\u003C\/em\u003E resulted in unstable proteins, suggesting that reduced \u003Cem\u003EG6PC2\u003C\/em\u003E protein in human pancreatic islets leads to reductions in FPG.\u003C\/p\u003E\u003Cp id=\u0022p-7\u0022\u003EProf Gloyn then discussed whether the T2DM-associated variants could alter the amount of gene transcript produced and thus whether the causal genes could be identified by this route. The majority of T2DM risk variants identified so far work through islet dysfunction [Voight BF et al. \u003Cem\u003ENat Genet\u003C\/em\u003E. 2010]. Using RNA and DNA extracted from human islets of 140 donors, Prof Gloyn and her colleagues determined that 1 of the T2DM risk variants influences \u003Cem\u003EZMIZ1\u003C\/em\u003E expression. Although the complete role of \u003Cem\u003EZMIZ1\u003C\/em\u003E in the pancreatic islet is still unclear, we now know that \u003Cem\u003EZMIZ1\u003C\/em\u003E is localized specifically to the islets in the human pancreas and is expressed at higher levels in islets from T2DM donors than from those without T2DM.\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EWhile modulation of target proteins could potentially decrease T2DM risk, it could also have negative effects. Prof Gloyn and her colleagues have been pursuing the question of whether human genetics can identify these effects.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EA 2008 study identified a coding variant (p.P446L) that resides in the glucokinase regulatory protein (GKRP) gene that is responsible for altered glucose levels, T2DM risk, and triglyceride levels [Orho-Melander M et al. \u003Cem\u003EDiabetes\u003C\/em\u003E. 2008]. The allele that reduces glucose levels and T2DM risk also increases triglyceride levels. This is likely due to the reduced ability of the GKRP-P446L protein to bind glucokinase in hepatocytes, leading to increased amounts of glucokinase in the cytoplasm [Rees MG et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E. 2011; Beer NL et al. \u003Cem\u003EHum Mol Genet\u003C\/em\u003E. 2009]. The resulting increase in glycolytic flux in the liver leads to reduced glucose levels and makes available substrates for de novo lipogenesis, leading to increased triglycerides. The effect of the variant is rather small, but individuals who have rare GKRP missense variants that result in a loss of function collectively have higher triglyceride levels than do people without these variants. Furthermore, an accumulation of rare GKRP variants has been reported in individuals with hypertriglyceridemia [Johansen CT et al. \u003Cem\u003ENat Genet\u003C\/em\u003E. 2010].\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EHigh-throughput assays demonstrated that a significant majority of functionally deleterious variants were collectively associated with hypertriglyceridemia and caused defects in glucokinase binding. Despite the fact that these rare variants are associated with higher triglyceride levels, they are not deterministic [Rees MG et al. \u003Cem\u003EHum Mol Genet\u003C\/em\u003E. 2014]. Prof Gloyn recommends monitoring lipid levels in phase 1 and 2 studies for GKRP small molecular disruptions (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E).\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022GKRP-P446L Protein Has Reduced Ability to Inhibit Liver Glucokinase\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-2093399522\u0022 data-figure-caption=\u0022GKRP-P446L Protein Has Reduced Ability to Inhibit Liver Glucokinase\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12062\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-11\u0022 class=\u0022first-child\u0022\u003EGKRP-P446L Protein Has Reduced Ability to Inhibit Liver Glucokinase\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003ESources: Rees SD et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E. 2011; Beer NL et al. \u003Cem\u003EHum Mol Genet\u003C\/em\u003E. 2009.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-12\u0022\u003EProf Gloyn also noted that evidence from epidemiologic, therapeutic, and genome-wide association studies demonstrates a possible link between diabetes and cancer [Voight BF et al. \u003Cem\u003ENat Genet\u003C\/em\u003E. 2010; Smith U, Gale EA. \u003Cem\u003EDiabetologia\u003C\/em\u003E. 2009; Gudmundsson J et al \u003Cem\u003ENat Genet\u003C\/em\u003E. 2007]. The tumor suppressor phosphatase and tensin homolog (\u003Cem\u003EPTEN\u003C\/em\u003E) antagonizes the AKT-PI3K pathway and is expressed in adipose tissue, liver, skeletal muscle, and pancreatic islets. In addition to being one of the most commonly somatically mutated genes in cancer, there are rare germline mutations in \u003Cem\u003EPTEN\u003C\/em\u003E that cause the rare cancer predisposition syndrome called Cowden syndrome, which is associated with an increased risk for breast and thyroid cancer.\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003E\n         \u003Cem\u003EPTEN\u003C\/em\u003E haploinsufficiency results in constitutive insulin sensitivity (\u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003EFigure 2\u003C\/a\u003E) and obesity (\u003Ca id=\u0022xref-fig-3-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F3\u0022\u003EFigure 3\u003C\/a\u003E). \u003Cem\u003EPTEN\u003C\/em\u003E mutation carriers are more obese than population-based controls due to augmented adiposity without corresponding changes in fat distribution. The molecular mechanism for the increase in insulin sensitivity in these patients seems to be increased signaling through the AKT-PI3 kinase pathway in adipose tissue.\u003C\/p\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022                PTEN Mutation Causes a Decrease in Insulin Release Following an Oral Glucose Tolerance Test\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-2093399522\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;                \u0026amp;lt;em\u0026amp;gt;PTEN\u0026amp;lt;\/em\u0026amp;gt; Mutation Causes a Decrease in Insulin Release Following an Oral Glucose Tolerance Test\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 2.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F2.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 2.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12036\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 2.\u003C\/span\u003E \n            \u003Cp id=\u0022p-14\u0022 class=\u0022first-child\u0022\u003E\n               \u003Cem\u003EPTEN\u003C\/em\u003E Mutation Causes a Decrease in Insulin Release Following an Oral Glucose Tolerance Test\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-2\u0022\u003E\n            \u003Cem\u003EPTEN\u003C\/em\u003E, phosphatase and tensin homolog.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-3\u0022\u003E\n            \u003Cem\u003EPTEN\u003C\/em\u003E mutation present in patient group.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-4\u0022\u003EFrom \u003Cem\u003ENew England Journal of Medicine\u003C\/em\u003E, Pal A et al. \u003Cem\u003EPTEN\u003C\/em\u003E Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity. 2012;367:1002\u20131011. Copyright \u00a9 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F3\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F3.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Obesity Higher in Patients With PTEN Mutation\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-2093399522\u0022 data-figure-caption=\u0022\u0026amp;lt;div xmlns=\u0026amp;quot;http:\/\/www.w3.org\/1999\/xhtml\u0026amp;quot;\u0026amp;gt;Obesity Higher in Patients With \u0026amp;lt;em\u0026amp;gt;PTEN\u0026amp;lt;\/em\u0026amp;gt; Mutation\u0026amp;lt;\/div\u0026amp;gt;\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 3.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F3.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F3.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 3.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F3.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12063\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 3.\u003C\/span\u003E \n            \u003Cp id=\u0022p-15\u0022 class=\u0022first-child\u0022\u003EObesity Higher in Patients With \u003Cem\u003EPTEN\u003C\/em\u003E Mutation\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-5\u0022\u003EBMI, body mass index; \u003Cem\u003EPTEN\u003C\/em\u003E, phosphatase and tensin homolog.\u003C\/q\u003E\u003Cq class=\u0022attrib\u0022 id=\u0022attrib-6\u0022\u003EFrom \u003Cem\u003ENew England Journal of Medicine\u003C\/em\u003E, Pal A et al. \u003Cem\u003EPTEN\u003C\/em\u003E Mutations as a Cause of Constitutive Insulin Sensitivity and Obesity. 2012;367:1002\u20131011. Copyright \u00a9 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-16\u0022\u003EIn summary, Prof Gloyn said that the study of human genetics can help to identify effective therapeutic targets and determine whether the development of targeted therapies should be directed toward an agonist or antagonist. Human genetics allows us to study the effect of a perturbation on a human phenotype over the lifetime of an individual and, by doing so, to identify adverse on-target effects.\u003C\/p\u003E\u003Cdiv id=\u0022F4\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F4.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022The editors would like to thank the many members of the European Association for the Study of Diabetes 2014 presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-2093399522\u0022 data-figure-caption=\u0022The editors would like to thank the many members of the European Association for the Study of Diabetes 2014 presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure4\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F4.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F4.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure4\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/14\/32\/6\/F4.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/12064\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\n            \u003Cp id=\u0022p-17\u0022 class=\u0022first-child\u0022\u003EThe editors would like to thank the many members of the European Association for the Study of Diabetes 2014 presenting faculty who generously gave their time to ensure the accuracy and quality of the articles in this publication.\u003C\/p\u003E\n         \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2014 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/14\/32\/6.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzorq2\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzorq2\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}