The Rise and the Fall of Betatrophin/ANGPTL8 as an Inducer of β-Cell Proliferation

Table 1

Selected early studies investigating the role of ANGPTL8 in obesity and diabetes.

Study design	Findings	Refs
Study was designed to identify new genes involved in lipid metabolism based on Lexicon-Genentech knockout database of genes that was generated for 3T3-L1 in vitro adipogenesis.	One of the first reports to study the role of ANGPTL8 or RIFL as they called it in lipid metabolism and highlighted its role in adipocyte differentiation and its similarity to ANGPTL3. They also showed that RIFL was induced by insulin.	[46]
Identification of lipid metabolism genes using transcriptomic analysis on liver and fat tissues extracted from mice treated with a high-fat diet or fasting using RNA-seq experiments.	ANGPTL8 or Lipasin was identified as a nutritionally regulated protein produced by the liver that regulates plasma lipid contents by affecting lipoprotein lipase activity.	[47]
Investigation of the ANGPTL8 role in lipid metabolism and identification of its variant in humans.	Identification of ANGPTL8 as a regulator of triglyceride in plasma through its interaction with ANGPTL3 that regulates the activity of lipoprotein lipase activity. They also identified an ANGPTL8 variant that was associated with reduced LDL and HDL levels.	[48]
Identification of insulin resistance related genes by inducing insulin resistance via treatment with S961 insulin receptor antagonist.	Identification of betatrophin as insulin resistance induced genes in the liver and white and brown adipose tissues in mice and humans. Its expression was increased over threefold in the liver of both ob/ob and db/db mice. It was also demonstrated to increase beta-cell proliferation and mass.	[49]
Use ANGPTL8 knockout model to investigate the role of this protein in beta-cell proliferation and glucose metabolism.	Based on their data they concluded that ANGPTL8 was not involved in controlling beta-cell growth in mice unlike what has been previously reported by Yi et al. [49].	[50]
Study the plasma level of ANGPTL8 in 33 people with T1D and their controls.	ANGPTL8 was increased in subjects with T1D.	[51]
Investigate changes in the level of ANGPTL8 in a large cohort of 1049 nondiabetic people and 556 people with T2D.	Increased ANGPTL8 in obese and T2D people. ANGPTL8 was positively associated with fasting blood glucose, HOMA-IR, and duration of diabetes.	[52]
Compare plasma level of ANGPTL8 in normal people with various glycemic indices as well as T2D people with their proper controls.	One of the only studies to show that ANGPTL8 level was decreased in obese people as well as people with T2D. This study used a different ELISA kit to measure plasma level of ANGPTL8 than what has been used by the other studies.	[53].