Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

Dwivedi, Om Prakash; Lehtovirta, Mikko; Hastoy, Benoît; Chandra, Vikash; Kleiner, Sandra; Jain, Deepak; Richard, Ann-Marie; Beer, Nicola L.; Krentz, Nicole A.J.; Prasad, Rashmi B.; Hansson, Ola; Ahlqvist, Emma; Krus, Ulrika; Artner, Isabella; Gomez, Daniel R.; Baras, Aris; Abaitua, Fernando; Champon, Benoite; Payne, Anthony; Moralli, Daniela; Thomsen, Soren K.; Krämer, Philipp; Spiliotis, Ioannis; Ramracheya, Reshma; Chabosseau, Pauline; Theodoulou, Andria; Cheung, Rebecca; Bunt, Martijn van de; Flannick, Jason; Trombetta, Maddalena; Bonora, Enzo; Wolheim, Claes B.; Sarelin, Leena; Bonadonna, Riccardo C.; Rorsman, Patrik; Rutter, Guy A.; Davies, Benjamin; Brosnan, Julia; McCarthy, Mark; Otonkoski, Timo; Lagerstedt, Jens O.; Gromada, Jesper; Gloyn, Anna L.; Tuomi, Tiinamaija; Groop, Leif

doi:10.1101/436030

Cited by 25 publications

(33 citation statements)

References 64 publications

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“…Strikingly, the vast majority affect insulin secretion rather than insulin action. Several laboratories, including our own, have provided possible mechanisms of action for some of the implicated genes, including TCF7L2, encoding the Wnt-regulated transcription factor [ 10 ], SLC30A8 encoding zinc transporter 8 (ZnT8, the secretory granule zinc transporter) [ 11 ], PAM , encoding peptidylglycine α-amidating monooxygenase [ 12 ] and STARD10 , encoding an intracellular lipid transporter [ 13 ]. The reader is referred to the recent review by Krentz and Gloyn [ 14 ] for a more comprehensive survey.…”

Section: Specialisations Of Beta Cell Metabolismmentioning

confidence: 99%

Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity

et al. 2020

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All forms of diabetes mellitus involve the loss or dysfunction of pancreatic beta cells, with the former predominating in type 1 diabetes and the latter in type 2 diabetes. Deeper understanding of the coupling mechanisms that link glucose metabolism in these cells to the control of insulin secretion is therefore likely to be essential to develop new therapies. Beta cells display a remarkable metabolic specialisation, expressing high levels of metabolic sensing enzymes, including the glucose transporter GLUT2 (encoded by SLC2A2) and glucokinase (encoded by GCK). Genetic evidence flowing from both monogenic forms of diabetes and genome-wide association studies for the more common type 2 diabetes, supports the importance for normal glucose-stimulated insulin secretion of metabolic signalling via altered ATP generation, while also highlighting unsuspected roles for Zn2+ storage, intracellular lipid transfer and other processes. Intriguingly, genes involved in non-oxidative metabolic fates of the sugar, such as those for lactate dehydrogenase (LDHA) and monocarboxylate transporter-1 ([MCT-1] SLC16A1), as well as the acyl-CoA thioesterase (ACOT7) and others, are selectively repressed (‘disallowed’) in beta cells. Furthermore, mutations in genes critical for mitochondrial oxidative metabolism, such as TRL-CAG1–7 encoding tRNALeu, are linked to maternally inherited forms of diabetes. Correspondingly, impaired Ca2+ uptake into mitochondria, or collapse of a normally interconnected mitochondrial network, are associated with defective insulin secretion. Here, we suggest that altered mitochondrial metabolism may also impair beta cell–beta cell communication. Thus, we argue that defective oxidative glucose metabolism is central to beta cell failure in diabetes, acting both at the level of single beta cells and potentially across the whole islet to impair insulin secretion.

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Section: Specialisations Of Beta Cell Metabolismmentioning

confidence: 99%

Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity

et al. 2020

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“…Ultimately, prioritized genes need to be validated in human models, as demonstrated for a mutation in SLC30A8 (encoding ZnT8). In a recall-by-genotype study with detailed metabolic phenotyping, it was shown that carriers were protected from T2D through enhanced glucose responsiveness and proinsulin conversion, making SLC30A8 /ZnT8 an appealing target for antidiabetic therapies 8 . The generation of new data and development of advanced technologies and analytical approaches will continue to facilitate the translation of a growing number of GWAS loci into meaningful biology and clinical targets in many years ahead.…”

Section: Boxmentioning

confidence: 99%

15 years of genome-wide association studies and no signs of slowing down

Loos

2020

Nat Commun

144

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Over the past 15 years, genome-wide association studies (GWASs) have generated a wealth of new information. Larger samples sizes, refined phenotypes and higher-resolution genome-screens will continue to drive gene discovery in years ahead. Meanwhile, GWAS loci are increasingly translated into new biology and opportunities for clinical care. When the Human Genome Project (HGP) was launched in 1993, the expectation was that genomics would transform clinical care, providing the insights needed to develop better diagnostic, prognostic, preventive, and therapeutic strategies for rare and common diseases. Upon completion of the HGP in 2003, the genome-wide association approach was hailed as the key gene discovery paradigm to translate these expectations into practice. Genome-wide association studies (GWASs) screen the genome for associations between millions of genetic variants and a disease or trait without any a priori hypothesis. As such, GWASs may reveal new genes and pathways not previously implicated in the disease pathology. While the very first GWAS was published in 2005 1 , it was the Wellcome Trust Case Control Consortium (WTCCC) that in 2007 set the stage for many more GWASs to come 2. With their pivotal paper, the WTCCC demonstrated that combining forces (large sample sizes), a rigorous study design (discovery and replication stages), and stringent criteria (multiple testing corrected significance level) were needed for reproducible discoveries. By the time Nature Communications was launched in April 2010, GWASs had already accelerated the rate of gene discovery to an unprecedented scale, identifying more than 3000 unique loci for over 250 disease/trait outcomes 3. These numbers increased exponentially over the subsequent 10 years, and to date, more than 4300 papers have reported on 4500 GWASs and over 55,000 unique loci for nearly 5000 diseases and traits 3. Summary statistics for most GWASs have been made publicly available 3 , and a number of user-friendly data portals allow scientists to query GWAS data freely (Box 1). Box 1 Selection of databases and browsers • Genome-wide association studies GWAS catalog https://www.ebi.ac.uk/gwas/ The GWAS catalog is a searchable database of SNP-trait associations for published GWAS.

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“…Genetic variants in the Zn 2+ transporter SLC30A8 ( ZNT8 ), present in the membrane of insulin granules, have been associated with T2D susceptibility ( 70 , 71 ). A rare loss of function mutation in ZNT8 protects against T2D, making this Zn 2+ transporter a potentially interesting therapeutic target ( 72 ).…”

Section: Beta Cell Insulin Secretion Defectsmentioning

confidence: 99%

Human Pluripotent Stem Cells to Model Islet Defects in Diabetes

2021

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Diabetes mellitus is characterized by elevated levels of blood glucose and is ultimately caused by insufficient insulin production from pancreatic beta cells. Different research models have been utilized to unravel the molecular mechanisms leading to the onset of diabetes. The generation of pancreatic endocrine cells from human pluripotent stem cells constitutes an approach to study genetic defects leading to impaired beta cell development and function. Here, we review the recent progress in generating and characterizing functional stem cell-derived beta cells. We summarize the diabetes disease modeling possibilities that stem cells offer and the challenges that lie ahead to further improve these models.

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Loss of ZnT8 function protects against diabetes by enhanced insulin secretion

Cited by 25 publications

References 64 publications

Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity

Metabolic and functional specialisations of the pancreatic beta cell: gene disallowance, mitochondrial metabolism and intercellular connectivity

15 years of genome-wide association studies and no signs of slowing down

Human Pluripotent Stem Cells to Model Islet Defects in Diabetes

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