Variants in the growth factor receptor-bound protein 10 (GRB10) gene were in a GWAS meta-analysis associated with reduced glucose-stimulated insulin secretion and increased risk of type 2 diabetes (T2D) if inherited from the father, but inexplicably reduced fasting glucose when inherited from the mother. GRB10 is a negative regulator of insulin signaling and imprinted in a parent-of-origin fashion in different tissues. GRB10 knock-down in human pancreatic islets showed reduced insulin and glucagon secretion, which together with changes in insulin sensitivity may explain the paradoxical reduction of glucose despite a decrease in insulin secretion. Together, these findings suggest that tissue-specific methylation and possibly imprinting of GRB10 can influence glucose metabolism and contribute to T2D pathogenesis. The data also emphasize the need in genetic studies to consider whether risk alleles are inherited from the mother or the father.

The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (b = 20.12, P = 0.03) and T2D and genetically determined lower LDL-C (b = 20.21, P = 5 3 10 26 ) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.Type 2 diabetes is associated with dyslipidemia (i.e., higher circulating concentrations of triglycerides and small, dense LDL cholesterol [LDL-C] and lower concentrations of HDL cholesterol [HDL-C]), but the causal relationship between dyslipidemia and type 2 diabetes has been difficult to disentangle (1). Most evidence suggests that altered lipid concentrations are secondary to insulin resistance (2) or other factors associated with both lipids and diabetes (e.g., adiposity), but some studies suggest that dyslipidemia could contribute to the pathogenesis of type 2 diabetes (3) through mechanisms related to impaired protection of b-cells or endoplasmic reticulum stress (4). Other studies of carriers of loss-of-function mutations in the ABCA1 gene have demonstrated that altered cholesterol concentrations could affect insulin secretion in humans, although with conflicting results (5,6).The relationship between lipid levels and diabetes is further complicated by the apparently causal link between statin therapy and increased risk of type 2 diabetes. A meta-analysis of randomized controlled trials and Mendelian randomization analysis (7) showed that statin treatment results in a slightly increased risk of diabetes. The Mendelian randomization study showed that a common allele in the 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) gene (encoding the target of statins) associated with lower LDL-C was also associated with a higher risk of diabetes and that this risk is potentially ...

CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretionAbels, Mia; Riva, Matteo; Bennet, Hedvig; Ahlqvist, Emma; Dyachok, Oleg; Nagaraj, Vini; Shcherbina, Liliya; Fred, Rikard G.; Poon, Wenny; Sörhede-Winzell, Maria; Fadista, Joao; Lindqvist, Andreas; Kask, Lena; Sathanoori, Ramasri; Dekker-Nitert, Marloes; Kuhar, Michael J.; Ahrén, Bo; Wollheim, Claes B.; Hansson, Ola; Tengholm, Anders; Fex, Malin; Renström, Erik; Groop, Leif; Lyssenko, Valeriya; Wierup, Nils Link to publication Citation for published version (APA): Abels, M., Riva, M., Bennet, H., Ahlqvist, E., Dyachok, O., Nagaraj, V., ... Wierup, N. (2016). CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion. Diabetologia, 59(9), 1928Diabetologia, 59(9), -1937Diabetologia, 59(9), . https://doi.org/10.1007 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. and if CART affects insulin-and glucagon secretion in vitro in humans and in vivo in mice.Methods CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and diabetic rodent models. Insulin-and glucagon secretion was examined in isolated islets and in vivo in mice. Ca 2+ oscillation patterns and exocytosis was studied in mouse islets.

Aims/hypothesis Genome-wide association studies (GWAS) have identified more than 65 genetic loci associated with risk of type 2 diabetes. However, the contribution of distorted parental transmission of alleles to risk of type 2 diabetes has been mostly unexplored. Our goal was therefore to search for parent-of-origin effects (POE) among type 2 diabetes loci in families. Methods Families from the Botnia study (n = 4,211, 1,083 families) were genotyped for 72 single-nucleotide polymorphisms (SNPs) associated with type 2 diabetes and assessed for POE on type 2 diabetes. The family-based Hungarian Transdanubian Biobank (HTB) (n = 1,463, >135 families) was used to replicate SNPs showing POE. Association of type 2 diabetes loci within families was also tested.Results Three loci showed nominal POE, including the previously reported variants in KCNQ1, for type 2 diabetes in families from Botnia (rs2237895: p POE = 0.037), which can be considered positive controls. The strongest POE was seen for rs7578597 SNP in the THADA gene, showing excess transmission of the maternal risk allele T to diabetic offspring (Botnia: p POE = 0.01; HTB p POE = 0.045). These data are consistent with previous evidence of allelic imbalance for expression in islets, suggesting that the THADA gene can be imprinted in a POE-specific fashion. Five CpG sites, including those flanking rs7578597, showed differential methylation between diabetic and non-diabetic donor islets. Conclusions/interpretation Taken together, the data emphasise the need for genetic studies to consider from which parent an offspring has inherited a susceptibility allele.

We show association of the purinergic signaling pathway in general and hypofunctioning P2X7 variants in particular with impaired glucose homeostasis in both mice and humans.

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