Heterozygous HNF1A mutations cause pancreatic-islet ␤-cell dysfunction and monogenic diabetes (MODY3). Hnf1␣ is known to regulate numerous hepatic genes, yet knowledge of its function in pancreatic islets is more limited. We now show that Hnf1a deficiency in mice leads to highly tissue-specific changes in the expression of genes involved in key functions of both islets and liver. To gain insights into the mechanisms of tissue-specific Hnf1␣ regulation, we integrated expression studies of Hnf1a-deficient mice with identification of direct Hnf1␣ targets. We demonstrate that Hnf1␣ can bind in a tissue-selective manner to genes that are expressed only in liver or islets. We also show that Hnf1␣ is essential only for the transcription of a minor fraction of its direct-target genes. Even among genes that were expressed in both liver and islets, the subset of targets showing functional dependence on Hnf1␣ was highly tissue specific. This was partly explained by the compensatory occupancy by the paralog Hnf1␤ at selected genes in Hnf1a-deficient liver. In keeping with these findings, the biological consequences of Hnf1a deficiency were markedly different in islets and liver. Notably, Hnf1a deficiency led to impaired large-T-antigen-induced growth and oncogenesis in ␤ cells yet enhanced proliferation in hepatocytes. Collectively, these findings show that Hnf1␣ governs broad, highly tissue-specific genetic programs in pancreatic islets and liver and reveal key consequences of Hnf1a deficiency relevant to the pathophysiology of monogenic diabetes.

Our data show that the pattern of circulating miRNAs is modified by defects in glucose metabolism in a similar manner in mice and humans. This circulating miRNA signature for prediabetes could be used as a new diagnostic tool, as well as to monitor response to intervention.

Heterotrimeric G proteins of the G i , G s , and G q family control a wide array of physiological functions primarily by regulating the activity of key intracellular second messenger-generating systems. ␣ subunits of the G 12 family, G␣ 12 and G␣ 13 , however, can promote cellular responses that are independent of conventional second messengers but that result from the activation of small GTP-binding proteins of the Rho family and their downstream targets. These findings led to the identification of a novel family of guanine-nucleotide exchange factors (GEFs) that provides a direct link between G␣ 12/13 and Rho stimulation. Recent observations suggest that many cellular responses elicited by G␣ q and its coupled receptors also require the functional activity of Rho. However, available evidence suggests that G␣ q may act on pathways downstream from Rho rather than by promoting Rho activation. These seemingly conflicting observations and the recent development of sensitive assays to assess the in vivo levels of active Rho prompted us to ask whether G␣ q and its coupled receptors can stimulate endogenous Rho. Here we show that the expression of activated forms of G␣ q and the stimulation of G qcoupled receptors or chimeric G␣ q molecules that respond to G i -linked receptors can promote a robust activation of endogenous Rho in HEK-293T cells. Interestingly, this response was not prevented by molecules interfering with the ability of G␣ 13 to stimulate its linked RhoGEFs, together suggesting the existence of a novel molecular mechanism by which G␣ q and the large family of G q -coupled receptors can regulate the activity of Rho and its downstream signaling pathways. G protein-coupled receptors (GPCRs)1 represent the largest family of cell surface molecules involved in signal transmission. They owe their name to their extensively studied interaction with heterotrimeric G proteins (␣, ␤, and ␥ subunits), which undergo conformational changes that lead to the exchange of GDP for GTP bound to the ␣ subunit upon receptor activation. Consequently, GTP-bound G␣ subunits of the G␣ i , G␣ s , G␣ q , and G␣ 12 family and free G ␤␥ subunits stimulate a variety of effector molecules thereby activating or inhibiting key second messenger-generating systems (1). However, recent evidence suggests that many cellular responses elicited by activation of heterotrimeric G proteins are not mediated by classical second messengers, but they involve not yet fully understood molecular mechanisms that result in the activation of small GTPbinding proteins of the Ras and Rho families. For example, it was observed that activated forms of G␣ 12 and G␣ 13 promote stress fiber formation, the assembly focal adhesions, the transcriptional activation of the serum responsive factor, and cellular transformation through Rho-dependent pathways without affecting conventional second messengers (2-4). These observations prompted the study of the underlying molecular mechanisms by which G␣ 12/13 activate Rho. In this regard, recent work has revealed that a nov...