• Angiopoietin-like protein 8
• Diabetes-associated cognitive dysfunction
• Microglia
• Neurons
• Paired immunoglobulin-like receptor B

• Animals
• Mice
• Cognitive Dysfunction/metabolism
• Cognitive Dysfunction/prevention & control
• Cognitive Dysfunction/etiology
• Signal Transduction/physiology
• Signal Transduction/drug effects
• Angiopoietin-like Proteins/metabolism
• Angiopoietin-like Proteins/genetics
• Humans
• Mice, Knockout
• Male
• Angiopoietin-Like Protein 8
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/metabolism
• Receptors, Immunologic/metabolism
• Receptors, Immunologic/genetics
• Mice, Inbred C57BL
• Synapses/metabolism
• Synapses/pathology
• Synapses/drug effects
• Peptide Hormones/metabolism
• Middle Aged
• Female

• 82270880 National Natural Science Foundation of China

• ANGPTL8
• Physical activity
• Weight loss

• Angiopoietin-Like Protein 8
• Angiopoietin-like Proteins
• Body Mass Index
• Exercise
• Humans
• Obesity/diagnosis
• Obesity/therapy
• Peptide Hormones
• Prospective Studies
• Weight Loss
• Weight Reduction Programs

• T32 DK007052 NIDDK NIH HHS

The liver, the largest solid visceral organ of the body, has numerous endocrine functions, such as direct hormone and hepatokine production, hormone metabolism, synthesis of binding proteins, and processing and redistribution of metabolic fuels. In the last 10 years, many new endocrine functions of the liver have been discovered. Advances in the classical endocrine functions include delineation of mechanisms of liver production of endocrine hormones [including 25-hydroxyvitamin D, insulin-like growth factor 1 (IGF-1), and angiotensinogen], hepatic metabolism of hormones (including thyroid hormones, glucagon-like peptide-1, and steroid hormones), and actions of specific binding proteins to glucocorticoids, sex steroids, and thyroid hormones. These studies have furthered insight into cirrhosis-associated endocrinopathies, such as hypogonadism, osteoporosis, IGF-1 deficiency, vitamin D deficiency, alterations in glucose and lipid homeostasis, and controversially relative adrenal insufficiency. Several novel endocrine functions of the liver have also been unraveled, elucidating the liver’s key negative feedback regulatory role in the pancreatic α cell-liver axis, which regulates pancreatic α cell mass, glucagon secretion, and circulating amino acid levels. Betatrophin and other hepatokines, such as fetuin-A and fibroblast growth factor 21, have also been discovered to play important endocrine roles in modulating insulin sensitivity, lipid metabolism, and body weight. It is expected that more endocrine functions of the liver will be revealed in the near future.

• Liver
• Endocrine function
• Hormone
• Amino acids
• Hepatokine
• Fibroblast growth factor 21

• Adipokines
• Cirrhosis
• Hepatokines
• Liver
• NAFLD
• NASH
• Obesity

• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/metabolism
• Drug Discovery
• Humans
• Intercellular Signaling Peptides and Proteins/metabolism
• Liver Neoplasms/etiology
• Liver Neoplasms/metabolism
• Non-alcoholic Fatty Liver Disease/complications
• Paracrine Communication
• Risk Factors

Hepatotropic viruses cause metabolic disturbances such as insulin resistance and hepatosteatosis. Moreover, metabolic factors, such as insulin resistance, obesity, and type 2 diabetes mellitus, increase the risk for hepatocellular carcinoma (HCC) in patients with virus-related liver cirrhosis. Cytokines secreted by the adipose tissue (adipokines) may be implicated in these metabolic disturbances, but there is little evidence regarding the role of adipokines in virus-related cirrhosis and HCC. Thus, we studied whether serum concentrations of selected adipokines were altered in patients with virus-related liver cirrhosis, including patients with HCC.

We included 43 patients with liver cirrhosis due to chronic hepatitis B or chronic hepatitis C. Of these patients, 36 had HCC and 7 did not have any malignant lesions. In addition to routine clinical and laboratory variables, we analyzed serum concentrations of betatrophin, insulin, vaspin, visfatin, and irisin.

Compared with healthy controls, patients with HCC had significantly increased vaspin concentrations and significantly reduced irisin concentrations. Compared with controls, patients with virus-related cirrhosis, with or without HCC, had significantly increased concentrations of insulin and betatrophin. The serum visfatin concentration was non-significantly higher in patients with virus-related cirrhosis than in controls. None of the studied adipokines was a significant predictor of HCC. Serum concentrations of the studied adipokines were not related to cirrhosis severity or HCC stage.

Metabolic parameters, including serum adipokine concentrations, are altered in patients with virus-related liver cirrhosis. Adipokines might be related to the HCC risk in these patients.

• adipokines
• cirrhosis
• hepatitis B virus
• hepatitis C virus
• hepatocellular carcinoma
• metabolic factors

We investigated the role of betatrophin in the etiopathogenesis of gestational diabetes mellitus (GDM) and its association with lipid and carbohydrate metabolism in patients with GDM and normoglycemic pregnant women.

A total of 60 patients [30 pregnant women with GDM (study group) and 30 healthy age-, body mass index-, and gestational agematched pregnant women (control group)] were included in this study. Serum betatrophin, fasting glucose, insulin, glycated hemoglobin A1c (HbA1c), and C-peptide levels, as well as lipid parameters, were measured.

Serum betatrophin, fasting glucose, HbA1c, insulin, and C-peptide levels were significantly higher in the GDM group than in the control group (p<0.001, p=0.009, p=0.013, p<0.001, and p<0.001, respectively). Levels of triglycerides and very-low-density lipoprotein cholesterol were significantly higher in the GDM group (p=0.020 and p=0.020, respectively), but total cholesterol and LDL cholesterol levels were similar in the two groups (p=0.810 and p=0.273, respectively). Betatrophin levels in the GDM group were correlated positively with insulin levels (r=0.336, p=0.009) and the homeostatic model assessment of insulin resistance (HOMA-IR) score (r=0.269, p=0.038), and negatively with the C-peptide levels (r=-0.399, p=0.002); they were not correlated with any other glucose or lipid parameters. Multivariate stepwise linear regression analysis demonstrated that insulin levels (β=0.134, p=0.013) and the HOMA-IR score (β=0.112, p=0.017) were associated independently with serum betatrophin levels.

These results demonstrate that serum betatrophin levels were significantly higher in pregnant women with GDM than in normoglycemic pregnant women. The levels of betatrophin were correlated significantly with insulin resistance parameters, which is a key feature of GDM pathophysiology.

• Betatrophin
• gestational diabetes mellitus
• insulin resistance

ANGPTL8/Betatrophin has been implicated in the regulation of both glucose and triglyceride metabolism. However, its role in regulating glucose metabolism by promoting β cell proliferation remains controversial, and its physiological functions and molecular targets are largely unknown. Hence, it is of great importance to make recombinant protein and test its effects on β cell mass directly. In this study, the mature form gene of human ANGPTL8/betatrophin was obtained through chemical synthesis on to the vector pUCE, and the fusion protein was expressed in the Transetta (DE3)/pEASY-E2-betatrophin strain. The inclusion bodies were solubilized in urea and purified by Ni–NTA affinity chromatography. The yield of purified ANGPTL8/betatrophin was approximately 20 mg per liter of culture medium. In vitro studies revealed that the recombinant ANGPTL8/betatrophin had no proliferation effect on MIN6 cells but promoted TG levels in HepG2 cells. This method to generate bioactive ANGPTL8/betatrophin is a simple, practical and user-friendly protocol.

• ANGPTL8/betatrophin
• Beta cell proliferation
• Recombinant expression
• Triglyceride level

• ANGPTL8
• Betatrophin
• Lifestyle intervention
• Obesity
• Type 2 diabetes

• Adult
• Angiopoietin-Like Protein 8
• Angiopoietin-like Proteins/metabolism
• Caloric Restriction/methods
• Combined Modality Therapy
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/metabolism
• Diabetes Mellitus, Type 2/therapy
• Exercise Therapy/methods
• Female
• Humans
• Hypoglycemic Agents/therapeutic use
• Male
• Middle Aged
• Obesity/complications
• Obesity/metabolism
• Obesity/therapy
• Overweight/complications
• Overweight/metabolism
• Overweight/therapy
• Peptide Hormones/metabolism

Betatrophin is a widely used diagnostic marker for type 2 diabetes mellitus (DM), but its clinical utility in diagnosing gestational DM (GDM) is unclear. We evaluated the relationship between betatrophin and the risk of GDM as well as the ability of betatrophin to predict postpartum type 2 DM (PDM).

In total, 386 patients were categorized into those with and without PDM. All underwent the oral glucose tolerance test while pregnant. Betatrophin was assessed to examine the diagnostic characteristics of GDM.

The betatrophin concentration was remarkably higher in patients with than without GDM. The patients were categorized into three groups; those with a betatrophin concentration of 300 to 600 pg/mL and >600 pg/mL had a higher risk of GDM after adjusting for body mass index, age, homeostatic model assessment–insulin resistance (HOMA-IR) concentration, and betatrophin concentration than those with a betatrophin concentration of <300 pg/mL. The HOMA-IR concentration tended to increase as the betatrophin concentration increased, and betatrophin was independently associated with GDM after adjusting for confounders. The betatrophin concentration was higher among pregnant patients with than without PDM.

Betatrophin has high sensitivity but low specificity for diagnosing GDM and may be a promising predictor of PDM.

• Gestational diabetes mellitus
• betatrophin
• biomarker
• homeostatic model assessment–insulin resistance
• postpartum diabetes mellitus
• prognosis