Hypoxia-inducible factor-1α regulates β cell function in mouse and human islets

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1α protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1α is required for normal β cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1α protein is present at low levels in mouse and human normoxic β cells and islets. Decreased levels of HIF-1α impaired glucosestimulated ATP generation and β cell function. C57BL/6 mice with β cell-specific Hif1a disruption (referred to herein as β-Hif1a-null mice) exhibited glucose intolerance, β cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1α levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in β-Hif1a-null mice. Increasing HIF-1α levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1α was bound to the Arnt promoter in a mouse β cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1α in β cell reserve and regulation of ARNT expression and demonstrate that HIF-1α is a potential therapeutic target for the β cell dysfunction of T2D. IntroductionThe transcription factor HIF-1α is important for a range of functions, including cellular responses to hypoxia and other stressors, angiogenesis, and fetal development (1-6). It has strong antiapoptotic effects (7-11) and is implicated in the pathogenesis of cardiovascular diseases and some cancers (12)(13)(14)(15)(16)(17)(18)(19)(20).HIF-1α is a member of the bHLH-PAS family (reviewed in refs. 2, 18, 21) and functions as an obligate dimer with other family members, including aryl hydrocarbon receptor (AhR) nuclear translocator (ARNT). We previously reported that ARNT was decreased in islets isolated from patients with type 2 diabetes (T2D) and that decreasing ARNT in Min6 cells or disrupting it in mouse β cells caused changes in gene expression and glucose-stimulated insulin secretion (GSIS) similar to those seen in islets isolated from humans with T2D (22). Recently, we reported a loss of ARNT expression in the livers of people with T2D, affecting dysregulation of gluconeogenesis (23). Though the specific ARNT partner which is important for its actions in β cells (or liver) is not known, candidates include AhR, HIF-1α, HIF-2α, HIF-3α, and circadian rhythm molecules, e.g., BMAL.

The Zinc Finger Protein ZBTB20 Regulates Transcription of Fructose-1,6-Bisphosphatase 1 and β Cell Function in Mice

“…27,28 Some factors (eg, hypoxia-inducible factor 1␣ and ARNT/hypoxiainducible factor 1␤) have been shown to contribute to altered function of diabetic ␤ cells. 29,30 Our results suggest that ZBTB20 may be another important player in ␤ cell dysfunction during the pathogenesis of T2DM.…”

Adipocyte iron regulates adiponectin and insulin sensitivity

“…Because of the association of iron both with insulin resistance and insulin deficiency (18,20,21,67,71,72), we reasoned that phlebotomy might improve both, leading to additive effects in decreasing diabetes risk. Phlebotomy in humans with IGT led to significant improvements in glucose tolerance and the glucose disposition index, a reflection of insulin secretion and sensitivity.…”

Label-free oxygen-metabolic photoacoustic microscopy in vivo

“…1 This metabolic phenotype has become the basis for tumor imaging by positron emission tomography (PET) using radioactively labeled oxygen. Many other pathological and physiological functions are also closely related to alterations of oxygen metabolism: examples include Alzheimer's disease, 3 diabetes, 4 burns, 5 obstructive pulmonary disease, 6 congestive heart failure, 7 aging, 8 sleeping, 9 and physiologic challenges. 10 Therefore, an accurate measurement of MRO 2 has the potential to provide a powerful tool for diagnosis and therapy of cancer and other diseases as well as for metabolism-related pathophysiological studies.…”