**3.1 ARNT/HIF-1β is reduced in human diabetic islets**

In 2005, a study published in *Cell* (Gunton et al., 2005) suggested that ARNT/HIF-1β, a transcription factor with previously unknown functions in beta-cells, plays a significant role in mediating human beta-cell dysfunction in type 2 diabetics. Genome-wide gene expression profiling of islets obtained from human non-diabetics and type 2 diabetics revealed that the expression levels of ARNT/HIF-1β was reduced by 90% under the diabetic conditions. This was associated with reduced expression levels of several ARNT/HIF-1β target genes involved in glycolysis and insulin signaling. Several enzymes in glycolysis, including phosphoglucomutase (PGM), phosphoglucose isomerase (G6PI), PFK and ALDO were expressed at significantly lower levels as compared to those observed in normal islets. The low ARNT/HIF-1β expression levels observed under diabetic conditions was also associated with low gene expression levels of several key regulators in insulin signaling, such as the insulin receptor (IR), insulin receptor substrate 2 (IRS2), and protein kinase B (Akt2). Another interesting observation made in this study was that MODY genes, HNF-1α and HNF- 4α, were poorly expressed in human islets obtained from type 2 diabetics. HNF-4α, the gene mutated in MODY1, has been shown to interact with ARNT/HIF-1β possibly providing a connection between the two transcription factors (Tsuchiya et al., 2002).

Fig. 2. Overview of gene regulation by ARNT/HIF-1β/HIF-1α complex in mammalian cells under normoxic and hypoxic conditions. In normoxic conditions, HIF-1α protein undergoes oxygen dependent hydroxylation by prolyl hydroxylases (PHD) and the hydroxylation site is recognized by pVHL, which targets the protein for ubiquitination by ubiquitin ligase, followed by degradation through ubiquitin proteasome pathway. During hypoxia, HIF-1α protein is not targeted for degradation and can translocate to the nucleus, where it heterodimerizes with ARNT/HIF-1β to form a stable transcriptional complex. The ARNT/HIF-1β/HIF-1α heterodimer then binds to the hypoxia response element (HRE) of target genes.

In 2005, a study published in *Cell* (Gunton et al., 2005) suggested that ARNT/HIF-1β, a transcription factor with previously unknown functions in beta-cells, plays a significant role in mediating human beta-cell dysfunction in type 2 diabetics. Genome-wide gene expression profiling of islets obtained from human non-diabetics and type 2 diabetics revealed that the expression levels of ARNT/HIF-1β was reduced by 90% under the diabetic conditions. This was associated with reduced expression levels of several ARNT/HIF-1β target genes involved in glycolysis and insulin signaling. Several enzymes in glycolysis, including phosphoglucomutase (PGM), phosphoglucose isomerase (G6PI), PFK and ALDO were expressed at significantly lower levels as compared to those observed in normal islets. The low ARNT/HIF-1β expression levels observed under diabetic conditions was also associated with low gene expression levels of several key regulators in insulin signaling, such as the insulin receptor (IR), insulin receptor substrate 2 (IRS2), and protein kinase B (Akt2). Another interesting observation made in this study was that MODY genes, HNF-1α and HNF- 4α, were poorly expressed in human islets obtained from type 2 diabetics. HNF-4α, the gene mutated in MODY1, has been shown to interact with ARNT/HIF-1β possibly providing a connection between the two

**3. ARNT/HIF-1β and type 2 diabetes** 

transcription factors (Tsuchiya et al., 2002).

**3.1 ARNT/HIF-1β is reduced in human diabetic islets** 

In order to rule out the possibility that the profound ARNT/HIF-1β down regulation in pancreatic beta-cells is not caused by the diabetic environment, Gunton and co-workers demonstrated that an identical gene profile was observed in a beta-cell-specific ARNT/HIF-1β knockout mouse (β-ARNT KO). β-ARNT KO mice exhibited impaired GSIS and glucose intolerance, with no significant change in beta-cell insulin content and islet mass. The finding that ARNT/HIF-1β knockout mice have normal islet mass suggests that this transcription factor does not play a role in beta-cell differentiation.

Overall, a combination of *in vivo* and *in vitro* studies in humans and rodents have provided us with convincing evidence that reduction in ARNT/HIF-1β expression in human pancreatic beta-cells has negative consequences in terms of beta-cell function and insulin secretion. However, the extent of ARNT/HIF-1β mediated regulation of gene transcription is complex since it has the potential to bind with multiple partners affecting a multitude of signaling pathways.
