Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1 b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply that melatonin physiologically serves to inhibit nocturnal insulin release.

Significance Prostate cancer is the most common malignancy and the third leading cancer-related cause of death among men of the Western world. Treatment options at advanced stages of the disease are scarce, and better therapies are in urgent need. In our study, we show that the clinically relevant lipid kinase phosphatidylinositol-4-phosphate 5-kinase-α (PIP5Kα) plays an important role in cancer cell invasion and survival by regulating the PI3K/AKT/androgen receptor pathways. Elevated levels of PIP5K1α contribute to cancer cell proliferation, survival, and invasion. In this context we introduce a newly developed compound, ISA-2011B, with promising anticancer effects by inhibiting the PIP5K1α-associated AKT pathways. Conclusively, we propose that PIP5K1α may be used as a potential therapeutic target for treatment of advanced prostate cancer.

Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors’, we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.

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.