Loss-of-function mutations in SLC30A8 protect against type 2 diabetes.

Neðst á síðunni er hægt að nálgast greinina í heild sinni með því að smella á hlekkinn View/OpenLoss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (-0.17 s.d., P = 4.6 × 10(-4)). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.US National Institutes of Health (NIH) Training 5-T32-GM007748-33 Doris Duke Charitable Foundation 2006087 Fulbright Diabetes UK Fellowship BDA 11/0004348 Broad Institute from Pfizer, Inc. NIH U01 DK085501 U01 DK085524 U01 DK085545 U01 DK085584 Swedish Research Council Dnr 521-2010-3490 Dnr 349-2006-237 European Research Council (ERC) GENETARGET T2D GA269045 ENGAGE 2007-201413 CEED3 2008-223211 Sigrid Juselius Foundation Folkh lsan Research Foundation ERC AdG 293574 Research Council of Norway 197064/V50 KG Jebsen Foundation University of Bergen Western Norway Health Authority Lundbeck Foundation Novo Nordisk Foundation Wellcome Trust WT098017 WT064890 WT090532 WT090367 WT098381 Uppsala University Swedish Research Council and the Swedish Heart- Lung Foundation Academy of Finland 124243 102318 123885 139635 Finnish Heart Foundation Finnish Diabetes Foundation, Tekes 1510/31/06 Commission of the European Community HEALTH-F2-2007-201681 Ministry of Education and Culture of Finland European Commission Framework Programme 6 Integrated Project LSHM-CT-2004-005272 City of Kuopio and Social Insurance Institution of Finland Finnish Foundation for Cardiovascular Disease NIH/NIDDK U01-DK085545 National Heart, Lung, and Blood Institute (NHLBI) National Institute on Minority Health and Health Disparities N01 HC-95170 N01 HC-95171 N01 HC-95172 European Union Seventh Framework Programme, DIAPREPP Swedish Child Diabetes Foundation (Barndiabetesfonden) 5U01DK085526 DK088389 U54HG003067 R01DK072193 R01DK062370 Z01HG000024info:eu-repo/grantAgreement/EC/FP7/20201

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

The rising global prevalence of obesity, metabolic syndrome, and type 2 diabetes has driven a sharp increase in non-alcoholic fatty liver disease (NAFLD), characterized by excessive fat accumulation in the liver. Approximately one-sixth of the NAFLD population progresses to non-alcoholic steatohepatitis (NASH) with liver inflammation, hepatocyte injury and cell death, liver fibrosis and cirrhosis. NASH is one of the leading causes of liver transplant, and an increasingly common cause of hepatocellular carcinoma (HCC), underscoring the need for intervention. The complex pathophysiology of NASH, and a predicted prevalence of 3–5% of the adult population worldwide, has prompted drug development programs aimed at multiple targets across all stages of the disease. Currently, there are no approved therapeutics. Liver-related morbidity and mortality are highest in more advanced fibrotic NASH, which has led to an early focus on anti-fibrotic approaches to prevent progression to cirrhosis and HCC. Due to limited clinical efficacy, anti-fibrotic approaches have been superseded by mechanisms that target the underlying driver of NASH pathogenesis, namely steatosis, which drives hepatocyte injury and downstream inflammation and fibrosis. Among this wave of therapeutic mechanisms targeting the underlying pathogenesis of NASH, the hormone fibroblast growth factor 21 (FGF21) holds considerable promise; it decreases liver fat and hepatocyte injury while suppressing inflammation and fibrosis across multiple preclinical studies. In this review, we summarize preclinical and clinical data from studies with FGF21 and FGF21 analogs, in the context of the pathophysiology of NASH and underlying metabolic diseases.</jats:p