Liver-Derived Systemic Factors Drive β Cell Hyperplasia in Insulin-Resistant States

Abstract

SUMMARY Integrative organ crosstalk regulates key aspects of energy homeostasis, and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that crosstalk between the liver and pancreatic islets modulates β cell growth in response to insulin resistance, we used the liver-specific insulin receptor knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, as well as in vitro islet culture approaches, we demonstrate that humoral, nonneural, non-cell-autonomous factor(s) induces β cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β cell growth factor(s) in insulin-resistant states.

Hepatic Insulin Resistance Following Chronic Activation of the CREB Coactivator CRTC2

“…Additionally, secreted factors such as hepatocyte growth factor or glucagon-like peptide-1 can induce ␤-cell replication (26 -28). It is also possible that the constitutively active expression of CRTC2 in the liver promotes transcription of a liver derived factor, which then promotes ␤-cell hyperplasia, such as that described by El Ouaamari et al in 2013 (29). Future studies should provide insight into this process.…”

Gα i/o -coupled receptor signaling restricts pancreatic β-cell expansion

“…Parasympathetic signaling through the vagus nerve also regulates β-cell mass (43)(44)(45)(46) and has been implicated in the regulation of β-cell mass by the liver (47), although liver-specific secreted factors (48, 49) also may regulate β-cell proliferation directly (49).…”

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

“…Interestingly, a systemic factor has been considered responsible for increasing the proliferation rate of old pancreatic beta cells when parabiosed to young mice [147]. Whether this factor is similar to the circulating factor in insulin-resistant states [4] has not been fully explored.…”

“…In favour of the former, several factors have been described as protecting beta cells in animal models, such as hepatocyte growth factor, gastric inhibitory polypeptide (GIP), insulin-like growth factor 1 (IGF-1), and prolactin. In terms of evidence for the latter, glucagon-like peptide 1 (GLP-1), liver-derived factors [4] and betatrophin (also termed angiopoietin-like 8, RIFL or lipasin) [5] have been reported to increase beta cell proliferation. While expansion of existing beta cells in vivo has mostly been explored in rodents [6,7], limited data from obese or insulinresistant humans also indicate a potential for islet mass expansion.…”