Editors' ChoiceType 2 Diabetes

HIF-1α: A New Target for Treating Diabetes?

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Science Translational Medicine  19 May 2010:
Vol. 2, Issue 32, pp. 32ec78
DOI: 10.1126/scitranslmed.3001275

The transcription factor hypoxia-inducible factor-1α (HIF-1α) is implicated in many biological processes and plays a key role in the regulation of cellular responses to hypoxia (oxygen deprivation) and other stressors. However, could it also be a key factor in regulating the function of insulin-producing pancreatic β cells—even in a nonstressed environment? New work by Cheng et al. indicates that it might indeed serve such a role.

These authors found that HIF-1α is present in normal human islets, associates with aryl hydrocarbon receptor nuclear translocator (ARNT)—a protein that plays a role in insulin secretion—and binds to the ARNT promoter, making it potentially transcriptionally active in the basal (nontoxic/nonhypoxic) state. They also showed that increasing HIF-1α levels increased the expression of ARNT and several key metabolic genes in islets (hormone-producing regions of the pancreas) from control subjects, normalized their expression in islets from subjects with type 2 diabetes, and improved glucose-stimulated insulin secretion. The authors then demonstrated that a targeted disruption of HIF-1α in β cells of mice (creating β-Hif1α–null mice) led to β-cell dysfunction, glucose intolerance, and impaired glucose-stimulated insulin secretion. Furthermore, increasing HIF-1α levels in control mice but not β-Hif1α–null mice improved glucose tolerance during exposure to a high-fat diet, demonstrating the importance of β-cell HIF-1α for this effect. The authors also showed that reducing Hif1α mRNA levels by using RNA interference in a pancreatic β-cell line markedly impaired β-cell function.

Taken together, these findings—from experiments using a pancreatic β-cell line, mouse islets, and human islets—suggest that HIF-1α may be an as yet unrecognized and important player in β-cell function, and that methods of increasing HNF-1α activity in β cells may be a new therapeutic strategy for type 2 diabetes, a condition that affects more than 20 million individuals in the United States alone.

K. Cheng et al., Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets. J. Clin. Invest. 3 May 2010 (10.1172/JCI35846). [Full Text]

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