Liquiritigenin Reduces Blood Glucose Level and Bone Adverse Effects in Hyperglycemic Adult Zebrafish.

Marta Carnovali,Massimo Mariotti,Ileana Terruzzi,Giuseppe Banfi,Livio Luzi

doi:10.3390/nu11051042

Abstract

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia that induces other pathologies including diabetic retinopathy and bone disease. Adult Danio rerio (zebrafish) represents a powerful model to study both glucose and bone metabolism. Then, the aim of this study was to evaluate the effects of liquiritigenin (LTG) on blood glucose level and diabetes complications in hyperglycemic adult zebrafish. LTG is a flavonoid extracted from Glycyrrhiza glabra roots which possess important antioxidant, anti-inflammatory, and anti-diabetic properties. During four weeks of glucose treatment, LTG significantly prevented the onset of the hyperglycemia in adult zebrafish. Moreover, hyperglycemic fish showed increased advanced glycation end-products (AGEs) and parathormone levels whereas LTG completely prevented both of these metabolic alterations. Large bone-loss areas were found in the scales of glucose-treated fish whereas only small resorption lacunae were detected after glucose/LTG treatment. Biochemical and histological tartrate resistant acid phosphatase (TRAP) assays performed on explanted scales confirmed that LTG prevented the increase of osteoclastic activity in hyperglycemic fish. The osteoblastic alkaline phosphatase (ALP) activity was clearly lost in scales of glucose-treated fish whereas the co-treatment with LTG completely prevented such alteration. Gene expression analysis showed that LTG prevents the alteration in crucial bone regulatory genes. Our study confirmed that LTG is a very promising natural therapeutic approach for blood glucose lowering and to contrast the development of bone complications correlated to chronic hyperglycemia.

Highlights

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia and impaired insulin secretion or action
Our study confirmed that LTG is a very promising natural therapeutic approach for blood glucose lowering and to contrast the development of bone complications correlated to chronic hyperglycemia
As expected in a diabetes animal model, we detected a significant increase of advanced glycation end-products (AGEs) in the blood of hyperglycemic fish by ELISA and co-treatment with LTG was able to suppress AGEs generation suggesting its potential ability to reduce hyperglycemia-induced complications

Summary

Introduction

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia and impaired insulin secretion or action. Chronic hyperglycemia affects a large variety of organs inducing several secondary pathologies including retinopathy and bone alterations [1]. Liquiritigenin (LTG) is a licorice-derived flavonoid (from Glycyrrhiza glabra) that is already tested in in vitro and in vivo models for treating many diseases, including diabetes [2,3]. Nutrients 2019, 11, 1042 recognized as an optimum treatment to attenuate diabetic complications derived from hyperglycemia. It has been demonstrated in vitro that LTG protects glomerular mesangial cells (HBZY-1) from high glucose-induced extracellular matrix accumulation, oxidative stress, and the inflammatory response by reducing the production of interleukin 1β (IL1β), interleukin 6 (IL-6), and activation of nuclear factor-kappa B (NF-kB) and nod-like receptor protein 3 (NLRP3) [4]. In vivo studies confirmed its anti-diabetic activity; for example, studies performed on streptozocin-induced diabetic mice have shown that LTG and isoliquiritigenin have a glucose-lowering effect measured through oral glucose tolerance test and induce a reduction of triglycerides [2,5]

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