Figure 2
Regulation and function of HIF in endocrine organs associated with type 2 diabetes mellitus. (A) The effects of HIF signaling
on glucose and lipid metabolism are more ambiguous, but there appears some link between hypoxia and T2DM development. The
process of glucose metabolism consumes robust oxygen; thus, β-cells encounter cellular hypoxia condition that activates HIF-1/2α.
Mice with β-cell-specific knockout Hif-1α, Hif-1β, or Vhl knockout show the impaired glucose metabolism features. (B) Adipose tissue expansion in obesity causes the hypoxic microenvironment.
Hypoxia activates the HIF-1α and HIF-2α cascades. HIF-1α increases adipose tissue fibrosis by upregulating collagen expression
and promoting the crosslinking of collagens, which ultimately results in inflammation and insulin resistance. Conversely,
HIF-2α has protective effect through opposing the HIF-1α pathway. Besides, HIF-2α induces angiogenesis, which improves the
oxygen level of adipose. (C) Hepatic lipid metabolism is a component of T2DM. Hypoxic hepatocytes, such as those in pericentral
zone, are more involved in lipogenesis and repression of β-oxidation. In experimental obesity models, intermittent hypoxia
exposure worsens the insulin intolerance and hepatic steatosis. Hepatocyte-specific Hif-1α knockout mice fed with high-fat diet exhibit glucose intolerance. Hepatic ablation of Hif-1β in mice increases the hepatic glucose production and impairs the glucose tolerance.